Pharmaceutical Compositions of Adsorbates of Amorphous Drug

ABSTRACT

Pharmaceutical compositions comprise a low-solubility drug adsorbed onto a high surface area substrate to form an adsorbate. The compositions in some embodiments include a concentration-enhancing polymer.

This application claims the benefit of priority of provisional PatentApplication Ser. No. 60/300,260 filed Jun. 22, 2001, which isincorporated herein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical compositions of alow-solubility drug and a high surface area substrate, wherein the drugand substrate are combined to form an adsorbate.

Low-solubility drugs often show poor bioavailability or irregularabsorption, the degree of irregularity being affected by factors such asdose level, fed state of the patient, and form of the drug. Increasingthe bioavailability of low-solubility drugs has been the subject of muchresearch. Increasing bioavailability hinges on improving theconcentration of the drug in solution to improve absorption.

It is well known that the amorphous form of a low-solubility drug thatis capable of existing in either the crystalline or amorphous form maytemporarily provide a greater aqueous concentration of drug relative tothe equilibrium concentration obtained by dissolution of drug in a useenvironment. Such amorphous forms may consist of the amorphous drugalone, a dispersion of the drug in a matrix material, or the drugadsorbed onto a substrate. It is believed that such amorphous forms ofthe drug may dissolve more rapidly than the crystalline form, oftendissolving faster than the drug can precipitate from solution. As aresult, the amorphous form may temporarily provide a greater-thanequilibrium concentration of drug.

While such amorphous forms may show initially enhanced concentration ofthe drug in a use environment, nevertheless the improved concentrationis often short-lived. Typically, the initially enhanced drugconcentration is only temporary and quickly returns to the lowerequilibrium concentration.

One problem with using the amorphous form of a drug is that the soliddrug may not be stable physically in the amorphous form. Often thecrystalline form of the drug has a lower free energy, and thus overtime, the amorphous drug will tend to crystallize. The rate ofcrystallization may be influenced by storage conditions, such astemperature and humidity, as well as the constituents of thecomposition.

D. Monkhouse, et al., Use of Adsorbents in Enhancement of DrugDissolution I, J. Pharm. Sciences, Vol. 61, No. 9, p. 1430 (1972),disclose forming adsorbents by mixing a drug and water-insolubleadsorbent such as fumed silicon dioxide or silicic acid, adding asufficient quantity of an organic solvent to dissolve the drug, and thenevaporating the solvent by a stream of filtered air. The authors reportimproved drug dissolution rates.

Matsui, et al., U.S. Pat. No. 4,772,627, disclose a ground mixture of apoorly soluble crystalline drug and an adsorbent. The mixture of drugand adsorbent is ground to obtain amorphous drug. Enhanced drugdissolution and drug absorption is reported

Denick, Jr. et al., U.S. Pat. No. 4,711,774, disclose an adsorbate of adrug and a complex magnesium aluminum silicate. The drug is dissolved ina solvent and added to magnesium aluminum silicate, and then dried. Theadsorbate is used to mask the taste of bitter drugs.

Lovrecich, U.S. Pat. No. 5,449,521, discloses amorphous drug absorbedonto a support material. The support material may be crosslinkedpolymers, linear polymers, water soluble complexing agents, and porousinorganic materials. The drug and support material are co-ground in amill with its grinding chamber saturated with the vapour of one or moresolvents able to solubilize the drug. The resulting product is dried andsieved. The resulting compositions are reported to have a reduced heatof fusion, a reduced melting point, an increased dissolution rate andincreased solubilization kinetices.

Accordingly, what is still desired is a composition comprising anamorphous drug form that is physically stable under typical storageconditions, and that may enhance the bioavailability of poorly solubledrugs. These needs and others that will become apparent to one ofordinary skill are met by the present invention, which is summarized anddescribed in detail below.

BRIEF SUMMARY OF THE INVENTION

The present invention overcomes the drawbacks of the prior art byproviding in a first aspect of the invention, pharmaceuticalcompositions comprising a solid adsorbate with a low-solubility drugadsorbed onto a substrate, said substrate having a surface area of atleast 20 m²/g, wherein at least a major portion of said drug in saidadsorbate is amorphous, wherein the adsorbate provides improvedconcentration of said drug in a use environment relative to aslow-evaporation control composition comprising said drug and saidsubstrate but formed by evaporation of solvent from a suspension of saiddrug in a solvent with said substrate suspended therein, saidevaporation of said solvent for formation of said slow-evaporationcontrol composition being conducted over a period of at least 30minutes.

In a second aspect, the present invention provides pharmaceuticalcompositions comprising a solid adsorbate with a low-solubility drugadsorbed onto a substrate, said substrate having a surface area of atleast 20 m²/g, wherein at least a major portion of said drug in saidadsorbate is amorphous; and a concentration-enhancing polymer.

In one preferred embodiment, the adsorbate provides improvedconcentration of said drug in a use environment relative to aslow-evaporation control composition comprising said drug and saidsubstrate but formed by evaporation of solvent from a suspension of saiddrug in a solvent with said substrate suspended therein, saidevaporation of said solvent for formation of said slow-evaporationcontrol composition being conducted over a period of at least 30minutes.

In another preferred embodiment, the adsorbate is more physically stablethan said slow-evaporation control composition.

In another preferred embodiment, the drug in said adsorbate has a glasstransition temperature substantially different from that of said drug inamorphous form alone that is not adsorbed to said substrate.

In yet another preferred embodiment, the drug is in the form of a layerof drug molecules adsorbed onto said substrate, said layer having athickness that is no greater than about 3-fold the diameter of saiddrug.

In another preferred embodiment, the drug is adsorbed onto saidsubstrate substantially in the form of a monolayer.

In still another preferred embodiment, the drug has improved physicalstability in said adsorbate relative to a control composition having anequivalent amount of said drug in amorphous form alone that is notadsorbed to said substrate. Preferably, the drug has a rate ofcrystallization in said adsorbate that is less than 90% of thecrystallization rate of said drug in amorphous form.

Another preferred embodiment relates to the drug in said adsorbatehaving a relative degree of improvement in chemical stability of atleast about 1.25 relative to said drug in amorphous form alone and notadsorbed to said substrate.

In another preferred embodiment, the drug in said adsorbate has arelative degree of improvement in chemical stability of at least 1.25relative to at least one of a first control composition having anequivalent amount of said drug in amorphous form mixed with saidconcentration-enhancing polymer and a second control compositionconsisting of a solid amorphous dispersion of an equivalent amount ofsaid drug and said concentration-enhancing polymer.

In still another preferred embodiment, the drug is acid-sensitive andsaid concentration-enhancing polymer is acidic.

In another preferred embodiment, the surface area of said substrate isat least 50 m²/g, preferably at least 180 m²/g.

In another preferred embodiment, the adsorbate is in the form ofagglomerates having a mean average diameter of from about 10 nm to about100 μm, preferably from about 10 nm to about 1 μm.

In another preferred embodiment, the substrate is an inorganic oxide,preferably SiO₂, TiO₂, ZnO₂, ZnO, Al₂O₃, or zeolite.

In yet another preferred embodiment, the substrate is a water insolublepolymer, preferably cross-linked polyvinyl pyrrolidinone, cross-linkedcellulose acetate phthalate, cross-linked hydroxypropyl methyl celluloseacetate succinate, microcrystalline cellulose, polyethylene/polyvinylalcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer,cross-linked carboxymethyl cellulose, sodium starch glycolate, orcross-linked styrene divinyl benzene.

In another preferred embodiment, the substrate is an activated carbon,preferably a carbonized polymer such as polyimides, polyarylonitrile,phenolic resins, cellulose acetate, regenerated cellulose, and rayon.

Another preferred embodiment includes the drug in said adsorbate assubstantially amorphous, preferably the drug is almost completelyamorphous.

In another preferred embodiment, the drug and saidconcentration-enhancing polymer are co-adsorbed onto said substrate,preferably, the drug and said polymer are substantially in the form ofan amorphous dispersion, more preferably, the dispersion issubstantially homogeneous.

In another preferred embodiment, the composition is a mixture of saidadsorbate and said concentration-enhancing polymer, preferably thecomposition is a mixture of particles of said adsorbate and particles ofsaid concentration-enhancing polymer. More preferably, the adsorbate andsaid concentration-enhancing polymer are each in respective regions.Preferably, the mixture is formed by wet-granulation and/ordry-granulation.

In another preferred embodiment, the concentration-enhancing polymer hasa hydrophobic portion and a hydrophilic portion.

In another preferred embodiment, the concentration-enhancing polymer isa cellulosic ionizable polymer, preferably hydroxypropyl methylcellulose succinate, cellulose acetate succinate, methyl celluloseacetate succinate, ethyl cellulose acetate succinate, hydroxypropylcellulose acetate succinate, hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropyl cellulose acetate phthalate succinate,cellulose propionate succinate, hydroxypropyl cellulose butyratesuccinate, hydroxypropyl methyl cellulose phthalate, carboxymethylcellulose, carboxyethyl cellulose, ethylcarboxymethyl cellulose,cellulose acetate phthalate, methyl cellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, ethylpicolinic acid cellulose acetate or blends thereof.

In another preferred embodiment, the concentration-enhancing polymer isan ionizable, non-cellulosic polymer, preferably carboxylic acidfunctionalized polymethacrylates, carboxylic acid functionalizedpolyacrylates, amine-functionalized polyacrylates, amine-fuctionalizedpolymethacrylates, proteins, carboxylic acid functionalized starches orblends thereof.

In yet another preferred embodiment, the concentration-enhancing polymeris a non-ionizable cellulosic polymer, preferably hydroxypropyl methylcellulose acetate, hydroxypropyl methyl cellulose, hydroxypropylcellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethylcellulose acetate, and hydroxyethyl ethyl cellulose or blends thereof.

In another preferred embodiment, the concentration-enhancing polymer isa non-ionizable, non-cellulosic polymer, preferably vinyl polymer orcopolymer having at least one substituent selected from the groupconsisting of hydroxyl, alkylacyloxy, and cyclicamido, vinyl copolymersof at least one hydrophilic, hydroxyl-containing repeat unit and atleast one hydrophobic, alkyl- or aryl-containing repeat unit, polyvinylalcohols that have at least a portion of their repeat units in theunhydrolyzed form, polyvinyl alcohol polyvinyl acetate copolymers,polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone, polyethylene polyvinyl alcohol copolymers,polyoxyethylene-polyoxypropylene block copolymers and blends thereof.

In another preferred embodiment, the concentration-enhancing polymer isa neutralized acidic polymer.

In still another preferred embodiment, the composition when administeredto a use environment provides a dissolution area under the concentrationversus time curve for a time period of at least 90 minutes between thetime of introduction to said use environment and about 270 minutesfollowing introduction to the use environment that is at least 1.25-foldthe corresponding area under the curve provided by a control compositioncomprising an equivalent amount of crystalline drug alone.

In another preferred embodiment, the composition when administered to ause environment provides a maximum concentration of said drug in saiduse environment that is at least 1.25-fold a maximum concentration ofsaid drug provided by a control composition comprising an equivalentamount of crystalline drug alone.

In another preferred embodiment, the composition when administered to ause environment provides a relative bioavailability of at least 1.25relative to a control composition consisting of an equivalent amount ofsaid drug in crystalline form alone.

In another preferred embodiment, the drug is selected from the groupconsisting of antihypertensives, antianxiety agents, anticlottingagents, anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,cholesterol-reducing agents, antiobesity agents, autoimmune disorderagents, anti-impotence agents, antibacterial and antifungal agents,hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's diseaseagents, antibiotics, anti-depressants, antiviral agents,anti-atherosclerotic agents, glycogen phosphorylase inhibitors, andcholesterol ester transfer protein,inhibitors.

In another preferred embodiment, the drug is[R—(R*S*)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamimo}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamide,5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide,[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, [2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl)-2(S),7-dihydroxy-7-methyl-octyl]amide, [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,5-(2-(4-(3-benzisothiazolyl)-piperazinyl)ethyl-6-chlorooxindole, orindomethacin.

A third aspect of the invention relates to methods of administering adrug comprising co-administering to a patient in need of said drug: (a)an adsorbate comprising a low-solubility drug adsorbed onto a substrate,said substrate having a surface area of at least 20 m²/g, wherein atleast a major portion of said drug in said adsorbate is amorphous; and(b) a concentration-enhancing polymer.

In a preferred embodiment, the adsorbate is administered separately fromsaid concentration-enhancing polymer or theconcentration-enhancingpolymer are administered at approximately the same time.

In another preferred embodiment, the adsorbate and saidconcentration-enhancing polymer are present in a single dosage form.

A fourth aspect of the present invention relates to methods for forminga pharmaceutical composition that include: (a) providing a substratehaving a surface area of at least 20 m²/g; (b) adding said substrate toa solvent to form a suspension and agitating said suspension; (c)dissolving a low-solubility drug in said solvent; and (d) rapidlyremoving said solvent from said suspension to form an adsorbatecomprising said low-solubility drug adsorbed onto said substrate,wherein at least a major portion of said drug in said adsorbate is inamorphous form.

In one preferred embodiment, the step of agitating comprises sonicatingsaid suspension.

In another preferred embodiment, the step of removing said solvent fromsaid suspension is accomplished by spray-drying said suspension.

In another preferred embodiment, the method further comprises the stepof adding a concentration-enhancing polymer to said suspension.

In another preferred embodiment, the method further comprises the stepof combining said adsorbate with a concentration-enhancing polymer.

In a fifth aspect, the present invention relates to methods for forminga pharmaceutical composition, comprising: (a) providing a substratehaving a surface area of at least 20 m²/g; (b) melting a low-solubilitydrug; (c)

combining said low-solubility drug with said substrate to form amixture; and (d) cooling said mixture so that said low-solubility drugis adsorbed onto said substrate to form an adsorbate, at least a majorportion of said drug in said adsorbate being in amorphous form.

In a preferred embodiment, the method further comprises the step ofcombining a concentration-enhancing polymer with said low-solubilitydrug and said substrate.

In another preferred embodiment, the method further comprises the stepof combining said adsorbate with a concentration-enhancing polymer.

In a sixth aspect, the present invention also relates to pharmaceuticalcompositions formed by the above-described methods.

In a seventh aspect, the present invention relates to a solid adsorbatecomprising a low solubility drug adsorbed onto a substrate, saidsubstrate having a surface area of at least 20 m²/g, wherein at least amajor portion of said drug in said adsorbate is amorphous, wherein saidadsorbate provides improved concentration of said drug in a useenvironment relative to an equivalent amount of a slow-evaporationcontrol composition.

In a preferred embodiment, the solid adsorbate further comprises aconcentration-enhancing polymer.

In yet another preferred embodiment, the solid adsorbate is combinedwith a concentration-enhancing polymer.

The composition in some embodiments provides improved stability of theamorphous drug in the adsorbate. In addition, in some embodiments, thecompositions are concentration-enhancing, providing improvedconcentration of drug in a use environment relative to a controlcomposition comprising an equivalent amount of crystalline drug alone.

One key to the present invention was the recognition by the inventorsthat the formation of a drug/substrate adsorbate, wherein a majorportion of the drug in the adsorbate is amorphous, leads to an initiallyenhanced concentration of drug in a use environment, and further, thatthis enhanced concentration can be sustained by interaction of the drugin solution with the adsorbate. Thus, without implying any particularmechanism of action, it is believed that the interaction of the drug insolution with the adsorbate inhibits precipitation or crystallization ofthe drug, allowing the initially enhanced concentration of drug insolution to be sustained rather than decrease rapidly over time to thatobtained when amorphous drug alone is dosed to the use environment.

For those aspects of the invention which include a concentrationenhancing polymer, the drug/substrate adsorbate andconcentration-enhancing polymer are present together in the useenvironment. Thus, without implying any particular mechanism of action,it is believed that the concentration-enhancing polymers of thisinvention may also act as crystallization or precipitation inhibitors.In some cases, the concentration-enhancing polymers may also interactwith drug to form various types of polymer-drug assemblies such asaggregates or colloids. In addition, polymer, drug and substrate may allinteract in solution to form various drug/polymer/substrate assembliessuch as aggregates or colloids.

Regardless of the mechanism, the compositions of the present inventionprovide improved concentration of drug in the use environment. Theadsorbate, when introduced to a use environment, provides an initialconcentration of drug that exceeds the equilibrium concentration ofdrug. The adsorbate and/or the concentration-enhancing polymer retardsthe rate at which the initially enhanced drug concentration falls to theequilibrium concentration. Thus, the compositions of the presentinvention provide a dissolutionarea-under-the-concentration-versus-time-curve (“AUC”) that is greaterthan that provided by crystalline drug alone. In preferred embodiments,the compositions of the present invention provide an AUC that is greaterthan that provided by the drug in amorphous form alone.

In compositions that include a concentration-enhancing polymer, thecompositions preferably provide an AUC or maximum drug concentrationthat exceeds that of a control composition that consists of amorphousdrug alone (that is, free from both the substrate and theconcentration-enhancing polymer). Preferably, the compositions providean AUC or a maximum drug concentration that exceeds that provided by acontrol consisting of drug/substrate adsorbate but free from theconcentration-enhancing polymer. Nevertheless, the advantages of theinvention may be obtained by merely retarding the rate at which theenhanced drug concentration falls to the equilibrium concentration, evenwithout increasing the maximum drug concentration relative to a controlcomposition.

As a result of improving the dissolution AUC, the compositions of thepresent invention may also provide enhanced bioavailability of the drugby increasing the concentration of drug which remains dissolved in theuse environment, particularly in the GI tract. Improving theconcentration of the drug in solution allows more rapid absorption ofdrug and, as a result, higher blood levels to be achieved. In some casesthis enhanced absorption rate enables an effective level of drug to bereached that might not be reached by administration of conventionalforms of the drug. In other cases, administration of the compositions ofthe invention allows effective blood levels to be reached at lower drugdosage levels, which in turn decreases the amount of drug that must bedosed, and reduces the blood level variability. Such compositions mayalso allow the size of the dosage form to be decreased, depending on theamount of substrate and/or polymer needed.

Furthermore, because the compositions of the present invention providefor a higher concentration of drug dissolved in the use environment, andbecause once a high drug concentration is achieved the concentrationtends to remain high due to inhibition of precipitation orcrystallization of the drug, the compositions may have a number ofpositive effects. First, in cases where the use environment is the GItract, the compositions of the present invention may show lessvariability in drug absorption as a result of variation in thefed/fasted state of the GI tract of the human or animal. Second, due toa prolonged high drug concentration in the GI tract, absorption of drugmay continue over a longer time period and an effective concentration ofdrug in the blood may be maintained over a longer time period.

In some embodiments, stabilizing the drug as an adsorbate of the drugand substrate and then combining the adsorbate with theconcentration-enhancing polymer provides another of the advantages ofthe present invention, which is to allow the use ofconcentration-enhancing polymers which, for whatever reason, are notsuitable for forming a molecular dispersion with the particular drug.The difficulty in forming a stable dispersion may be due to adverseinteractions between the drug and polymer in the dispersion, resultingin chemical and/or physical instability of the drug in the dispersion.For example, although an acidic cellulosic polymer may provide superiorconcentration-enhancement for some drugs, such polymers may chemicallydegrade acid-sensitive drugs when present in the dispersion.

The present invention solves this problem by forming an adsorbate of thedrug and a substrate, and then combines the adsorbate with theconcentration-enhancing polymer to form the composition. This providesthe benefit of improved drug stability while at the same time providingthe additional level of concentration-enhancement conferred by thepresence of the concentration-enhancing polymer.

The foregoing and other objectives, features, and advantages of theinvention will be more readily understood upon consideration of thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed toward adsorbates of a low-solubilitydrug and a high surface area substrate. The compositions may optionallyinclude concentration-enhancing polymers. Suitable drugs, substrates,and concentration-enhancing polymers, as well as methods for preparingthe compositions, are discussed in detail below.

The Drug

The term “drug” is conventional, denoting a compound having beneficialprophylactic and/or therapeutic properties when administered to ananimal, especially humans. The drug does not need to be a low-solubilitydrug in order to benefit from this invention, although low-solubilitydrugs represent a preferred class for use with the invention. Even adrug that nonetheless exhibits appreciable solubility in the desiredenvironment of use can benefit from the increasedsolubility/bioavailability made possible by this invention if it reducesthe size of the dose needed for therapeutic efficacy or increases therate of drug absorption in cases where a rapid onset of the drug'seffectiveness is desired.

Preferably, the drug is a “low-solubility drug,” meaning that the drugmay be either “substantially water-insoluble,” which means that the drughas a minimum aqueous solubility at physiologically relevant pH (e.g.,pH 1-8) of less than 0.01 mg/mL, “sparingly water-soluble,” that is, hasan aqueous solubility up to about 1 to 2 mg/mL, or even low to moderateaqueous-solubility, having an aqueous-solubility from about 1 mg/mL toas high as about 20 to 40 mg/mL. The invention finds greater utility asthe solubility of the drug decreases. Thus, compositions of the presentinvention are preferred for low-solubility drugs having a solubility ofless than 10 mg/mL, more preferred for low-solubility drugs having asolubility of less than 1 mg/mL, and even more preferred forlow-solubility drugs having a solubility of less than 0.1 mg/mL. Ingeneral, it may be said that the drug has a dose-to-aqueous solubilityratio greater than 10 mL, and more typically greater than 100 mL, wherethe drug solubility (mg/mL) is the minimum value observed in anyphysiologically relevant aqueous solution (e.g., those with pH valuesbetween 1 and 8) including USP simulated gastric and intestinal buffers,and dose is in mg. Thus, a dose-to-aqueous solubility ratio may becalculated by dividing the dose (in mg) by the solubility (in mg/mL).

Preferred classes of drugs include, but are not limited to,antihypertensives, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,cholesterol-reducing agents, anti-atherosclerotic agents, antiobesityagents, autoimmune disorder agents, anti-impotence agents, antibacterialand antifungal agents, hypnotic agents, anti-Parkinsonism agents,anti-Alzheimer's disease agents, antibiotics, anti-depressants,antiviral agents, glycogen phosphorylase inhibitors, and cholesterolester transfer protein inhibitors.

Each named drug should be understood to include the neutral form of thedrug, pharmaceutically acceptable salts, as well as prodrugs. Specificexamples of antihypertensives include prazosin, nifedipine, amlodipinebesylate, trimazosin and doxazosin; specific examples of a bloodglucose-lowering agent are glipizide and chlorpropamide; a specificexample of an anti-impotence agent is sildenafil and sildenafil citrate;specific examples of antineoplastics include chlorambucil, lomustine andechinomycin; a specific example of an imidazole-type antineoplastic istubulazole; a specific example of an anti-hypercholesterolemic isatorvastatin calcium; specific examples of anxiolytics includehydroxyzine hydrochloride and doxepin hydrochloride; specific examplesof anti-inflammatory agents include betamethasone, prednisolone,aspirin, piroxicam, valdecoxib, carprofen, celecoxib, flurbiprofen and(+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea;a specific example of a barbiturate is phenobarbital; specific examplesof antivirals include acyclovir, nelfinavir, and virazole; specificexamples of vitamins/nutritional agents include retinol and vitamin E;specific examples of beta blockers include timolol and nadolol; aspecific example of an emetic is apomorphine; specific examples of adiuretic include chlorthalidone and spironolactone; a specific exampleof an anticoagulant is dicumarol; specific examples of cardiotonicsinclude digoxin and digitoxin; specific examples of androgens include17-methyltestosterone and testosterone; a specific example of a mineralcorticoid is desoxycorticosterone; a specific example of a steroidalhypnotic/anesthetic is alfaxalone; specific examples of anabolic agentsinclude fluoxymesterone and methanstenolone; specific examples ofantidepression agents include sulpiride,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine,3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine,pyroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; specificexamples of antibiotics include carbenicillin indanylsodium,bacampicillin hydrochloride, troleandomycin, doxycyline hyclate,ampicillin and penicillin G; specific examples of anti-infectivesinclude benzalkonium chloride and chlorhexidine; specific examples ofcoronary vasodilators include nitroglycerin and mioflazine; a specificexample of a hypnotic is etomidate; specific examples of carbonicanhydrase inhibitors include acetazolamide and chlorzolamide; specificexamples of antifungals include econazole, terconazole, fluconazole,voriconazole, and griseofulvin; a specific example of an antiprotozoalis metronidazole; specific examples of anthelmintic agents includethiabendazole and oxfendazole and morantel; specific examples ofantihistamines include astemizole, levocabastine, cetirizine,decarboethoxyloratadine and cinnarizine; specific examples ofantipsychotics include ziprasidone, olanzepine, thiothixenehydrochloride, fluspirilene, risperidone and penfluridole; specificexamples of gastrointestinal agents include loperamide and cisapride;specific examples of serotonin antagonists include ketanserin andmianserin; a specific example of an anesthetic is lidocaine; a specificexample of a hypoglycemic agent is acetohexamide; a specific example ofan anti-emetic is dimenhydrinate; a specific example of an antibacterialis cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA;specific examples of anti-Alzheimer's Disease agents are THA anddonepezil; a specific example of an anti-ulcer agent/H2 antagonist isfamotidine; specific examples of sedative/hypnotic agents includechlordiazepoxide and triazolam; a specific example of a vasodilator isalprostadil; a specific example of a platelet inhibitor is prostacyclin;specific examples of ACE inhibitor/antihypertensive agents includeenalaprilic acid and lisinopril; specific examples of tetracyclineantibiotics include oxytetracycline and minocycline; specific examplesof macrolide antibiotics include erythromycin, clarithromycin, andspiramycin; a specific example of an azalide antibiotic is azithromycin;specific-examples of glycogen phosphorylase inhibitors include[R—(R*S*)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamideand 5-chloro-1 H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide; and specific examples of cholesterol ester transferprotein (CETP) inhibitors include [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, [2R,4S] 4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, [2R, 4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

The invention is not limited by any particular structure or group ofCETP inhibitors. Rather, the invention has general applicability to CETPinhibitors as a class, the class tending to be composed of compoundshaving low solubility. Compounds which may be the subject of theinvention may be found in a number of patents and publishedapplications, including DE 19741400 A1; DE 19741399 A1; WO 9914215 A1;WO 9914174; DE 19709125 A1; DE 19704244 A1; DE 19704243 A1; EP 818448A1; WO 9804528 A2; DE 19627431 A1; DE 19627430 A1; DE 19627419 A1; EP796846 A1; DE 19832159; DE 818197; DE 19741051; WO 9941237 A1; WO9914204 A1; WO 9835937 A1; JP 11049743; WO 200018721; WO 200018723; WO200018724; WO 200017164; WO 200017165; WO 200017166; EP 992496; and EP987251, all of which are hereby incorporated by reference in theirentireties for all purposes.

The invention is useful for CETP inhibitors that have sufficiently lowaqueous solubility, low bioavailability or slow rate of absorption suchthat it is desirable to increase their concentration in an aqueousenvironment of use. Therefore, anytime one finds it desirable to raisethe aqueous concentration of the CETP inhibitor in a use environment,the invention will find utility. The CETP inhibitor is “substantiallywater-insoluble” which means that the CETP inhibitor has a minimumaqueous solubility of less than about 0.01 mg/mL (or 10 μg/ml) at anyphysiologically relevant pH (e.g., pH 1-8) and at about 22° C. (Unlessotherwise specified, reference to aqueous solubility herein and in theclaims is determined at about 22° C.) Compositions of the presentinvention find greater utility as the solubility of the CETP inhibitorsdecreases, and thus are preferred for CETP inhibitors with solubilitiesless than about 2 μg/mL, and even more preferred for CETP inhibitorswith solubilities less than about 0.5 μg/mL. Many CETP inhibitors haveeven lower solubilities (some even less than −0.1 μg/mL), and requiredramatic concentration enhancement to be sufficiently bioavailable uponoral dosing for effective plasma concentrations to be reached atpractical doses.

In general, it may be said that the CETP inhibitor has a dose-to-aqueoussolubility ratio greater than about 100 mL, where the solubility (mg/mL)is the minimum value observed in any physiologically relevant aqueoussolution (e.g., those with pH values from 1 to 8) including USPsimulated gastric and intestinal buffers, and dose is in mg.Compositions of the present invention, as mentioned above, find greaterutility as the solubility of the CETP inhibitor decreases and the doseincreases. Thus, the compositions are preferred as thedose-to-solubility ratio increases, and thus are preferred fordose-to-solubility ratios greater than 1000 mL, and more preferred fordose-to-solubility ratios greater than about 5000 ml. Thedose-to-solubility ratio may be determined by dividing the dose (in mg)by the aqueous solubility (in mg/ml).

Oral delivery of many CETP inhibitors is particularly difficult becausetheir aqueous solubility is usually extremely low, typically being lessthan 2 μg/ml, often being less than 0.1 μg/mi. Such low solubilities area direct consequence of the particular structural characteristics ofspecies that bind to CETP and thus act as CETP inhibitors. This lowsolubility is primarily due to the hydrophobic nature of CETPinhibitors. Clog P, defined as the base 10 logarithm of the ratio of thedrug solubility in octanol to the drug solubility in water, is a widelyaccepted measure of hydrophobicity. In general, Clog P values for CETPinhibitors are greater than 4 and are often greater than 5 to 7. Thus,the hydrophobic and insoluble nature of CETP inhibitors as a class posea particular challenge for oral delivery. Achieving therapeutic druglevels in the blood by oral dosing of practical quantities of druggenerally requires a large enhancement in drug concentrations in thegastrointestinal fluid and a resulting large enhancement inbioavailability. Such enhancements in drug concentration ingastrointestsinal fluid typically need to be at least about 10-fold andoften at least about 50-fold or even at least about 200-fold to achievedesired blood levels. Surprisingly, the dispersions of the presentinvention have proven to have the required large enhancements in drugconcentration and bioavailability.

In contrast to conventional wisdom, the relative degree of enhancementin aqueous concentration and bioavailability generally improves for CETPinhibitors as solubility decreases and hydrophobocity increases. Infact, the inventors have recognized a subclass of these CETP inhibitorsthat are essentially aqueous insoluble, highly hydrophobic, and arecharacterized by a set of physical properties. This subclass exhibitsdramatic enhancements in aqueous concentration and bioavailability whenformulated using the compositions of the present invention.

The first property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is extremely low aqueous solubility. Byextremely low aqueous solubility is meant that the minimum aqueoussolubility at physiologically relevant pH (pH of 1 to 8) is less thanabout 10 μg/ml and preferably less than about 1 μg/ml.

A second property is a very high does-to-solubility ratio. Extremely lowsolubility often leads to poor or slow absorption of the drug from thefluid of the gastrointestinal tract, when the drug is dosed orally in aconventional manner. For extremely low solubility drugs, poor absorptiongenerally becomes progressively more difficult as the dose (mass of druggiven orally) increases. Thus, a second property of this subclass ofessentially insoluble, hydrophobic CETP inhibitors is a very high dose(in mg) to solubility (in mg/ml) ratio (ml). By “very highdose-to-solubility ratio” is meant that the dose-to-solubility ratio hasa value of at least 1000 ml, and preferably at least 5,000 ml, and morepreferably at least 10,000 ml.

A third property of this subclass of essentially insoluble, hydrophobicCETP inhibitors is that they are extremely hydrophobic. By extremelyhydrophobic is meant that the Clog P value of the drug, has a value ofat least 4.0, preferably a value of at least 5.0, and more preferably avalue of at least 5.5.

A fourth property of this subclass of essentially insoluble CETPinhibitors is that they have a low melting point. Generally, drugs ofthis subclass will have a melting point of about 150° C. or less, andpreferably about 140° C. or less.

Primarily, as a consequence of some or all of these four properties,CETP inhibitors of this subclass typically have very low absolutebioavailabilities. Specifically, the absolute bioavailibility of drugsin this subclass when dosed orally in their undispersed state is lessthan about 10% and more often less than about 5%.

Turning now to the chemical structures of specific CETP inhibitors, oneclass of CETP inhibitors that finds utility with the present inventionconsists of oxy substituted4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines having the FormulaI

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;

-   wherein R_(I-1) is hydrogen, Y_(I), W_(I)-X_(I), W_(I)-Y_(I);-   wherein W_(I) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;-   X_(I) is —O—Y_(I), —S—Y_(I), —N(H)—Y, or —N—(Y_(I))₂;

wherein Y_(I) for each occurrence is independently Z_(I) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(I);

wherein Z_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxyl, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(I-3) is hydrogen or Q_(I);

wherein Q_(I) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I);

wherein V_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(I) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carbamoyl, mono-N- or di-N,N—(C₁-C₆) alkylcarbamoyl, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(I-4) is Q_(I-1) or V_(I-1)

wherein Q_(I-1) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I-1);

wherein V_(I-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(I-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-Cr₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein either R_(I-3) must contain V_(I) or R_(I-4) must containV_(I-1); and R_(I-5), R_(I-6), R_(I-7) and R_(I-8) are eachindependently hydrogen, hydroxy or oxy wherein said oxy is substitutedwith T_(I) or a partially saturated, fully saturated or fullyunsaturated one to twelve membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen and said carbon is optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(I);

wherein T_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines.

Compounds of Formula I and their methods of manufacture are disclosed incommonly assigned U.S. Pat. Nos. 6,140,342, 6,362,198, and EuropeanPatent publication 987251, all of which are incorporated herein byreference in their entireties for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula I:

[2R,4S] 4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[2R,4S]4-[(3,5-dinitro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(2,6-dichloro-pyridin-4-ylmethyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2,2,2-trifluoro -ethylester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,

[2R,4S](3,5-bis-trifluoromethyl-benzyl)-(1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid methyl ester;

[2R,4S] (3,5-bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester; and

[2R,4S](3,5-bis-trifluoromethyl-benzyl)-[1-(2-ethyl-butyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid methyl ester,hydrochloride.

Another class of CETP inhibitors that finds utility with the presentinvention consists of4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula II

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;

-   wherein R_(II-1) is hydrogen, Y_(II), W_(II)-X_(II), W_(II)-Y_(II);-   wherein W_(II) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;-   X_(II) is —O—Y_(II), —S—Y_(II), —N(H)—Y_(II), or —N—(Y_(II))₂;

wherein Y_(II) for each occurrence is independently Z_(II) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(II);

Z_(II) is a partially saturated, fully saturated or fully unsaturatedthree to twelve membered ring optionally having one to four heteroatomsselected independently from oxygen, sulfur and nitrogen, or a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

wherein said Z_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl is also optionally substituted with from one to ninefluorines;

R_(II-3) is hydrogen or Q_(II);

wherein Q_(II) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II);

wherein V_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(II) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N—(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are optionally substitutedwith from one to nine fluorines;

R_(II-4) is Q_(II-1) or V_(II-1)

wherein Q_(II-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II-1);

wherein V_(II-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(II-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isoptionally substituted with from one to nine fluorines;

wherein either R_(II-3) must contain V_(II) or R_(II-4) must containV_(II-1); and R_(II-5), R_(II-6), R_(II-7) and R_(II-8) are eachindependently hydrogen, a bond, nitro or halo wherein said bond issubstituted with T_(II) or a partially saturated, fully saturated orfully unsaturated (C₁-C₁₂) straight or branched carbon chain whereincarbon may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(II);

wherein T_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C6)alkyl substituent is also optionally substituted with from one tonine fluorines;

provided that at least one of substituents R_(II-5), R_(II-6), R_(II-7)and R_(II-8) is not hydrogen and is not linked to the quinoline moietythrough oxy.

Compounds of Formula II and their methods of manufacture are disclosedin commonly assigned U.S. Pat. No. 6,147,090, U.S. patent applicationSer. No. 09/671,400 filed Sep. 27, 2000, and PCT Publication No.WO00/17166, all of which are incorporated herein by reference in theirentireties for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula II:

[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2,6,7-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-i-carboxylic acid ethyl ester;

[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; and

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of annulated4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula III

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;

-   wherein R_(III) is hydrogen, Y_(III), W_(III)-X_(III),    W_(III)-Y_(III);-   wherein W_(III) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;-   X_(III) is —O—Y_(III), —S—Y_(III), —N(H)—Y_(III) or —N—(Y_(III))₂;

Y_(III) for each occurrence is independently Z_(III) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(III);

wherein Z_(III) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(III) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl optionally substituted with from one to nine fluorines;

R_(III-3) is hydrogen or Q_(III);

wherein Q_(III) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III);

wherein V_(III) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(III) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N—(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl are optionally substituted with from oneto nine fluorines;

R_(III-4) is Q_(III-1) or V_(III-1);

wherein Q_(III-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III-1);

wherein V_(III-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(III-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituentoptionally having from one to nine fluorines;

wherein either R_(III-3) must contain V_(III) or R_(III-4) must containV_(III-1); and R_(III-5) and R_(III-6), or R_(III-6) and R_(III-7),and/or R_(III-7) and R_(III-8) are taken together and form at least onefour to eight membered ring that is partially saturated or fullyunsaturated optionally having one to three heteroatoms independentlyselected from nitrogen, sulfur and oxygen;

wherein said ring or rings formed by R_(III-5) and R_(III-6), orR_(III-6) and R_(III-7), and/or R_(III-7) and R_(III-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆) alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said (C₁-C₆)alkylsubstituent optionally having from one to nine fluorines;

provided that the R_(III-5), R_(III-6), R_(III-7) and/or R_(III-8), asthe case may be, that do not form at least one ring are eachindependently hydrogen, halo, (C₁-C₆)alkoxy or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines.

Compounds of Formula III and their methods of manufacture are disclosedin commonly assigned U.S. Pat. Nos. 6,147,089, 6,310,075, and EuropeanPatent Application No. 99307240.4 filed Sep. 14, 1999, all of which areincorporated herein by reference in their entireties for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula III:

[2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid ethyl ester;

[6R, 8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-1H-2-thia-5-aza-cyclopenta[b]naphthalene-5-carboxylicacid ethyl ester;

[6R, 8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-2H-furo[2,3-g]quinoline-5-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,8-tetrahydro-2H-furo[3,4-g]quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinoline-1-carboxylicacid propyl ester;

[7R,9S]9-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methyl-1,2,3,7,8,9-hexahydro-6-aza-cyclopenta[a]naphthalene-6-carboxylicacid ethyl ester; and

[6S,8R]6-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-methyl-1,2,3,6,7,8-hexahydro-9-aza-cyclopenta[a]naphthalene-9-carboxylicacid ethyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of4-carboxyamino-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula IV

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;

-   wherein R_(IV-1) is hydrogen, Y_(IV), W_(IV)-X_(IV) or    W_(IV)-Y_(IV);-   wherein W_(IV) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;-   X_(IV) is —O—Y_(IV), —S—Y_(IV), —N(H)—Y_(IV) or —N—(Y_(IV))₂;

wherein Y_(IV) for each occurrence is independently Z_(IV) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(IV);

wherein Z_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; R_(IV-2) is a partially saturated, fully saturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(IV-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(IV-2) ring is optionally attached through (C₁-C₄)alkyl;

wherein said R_(IV-2) ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

with the proviso that R_(IV-2) is not methyl;

R_(IV-3) is hydrogen or Q_(IV);

wherein Q_(IV) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV);

wherein V_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(IV) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N—(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(IV-4) is Q_(IV-1) or V_(IV-1);

wherein Q_(IV-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV-1);

wherein V_(IV-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(IV-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein either R_(IV-3) must contain V_(IV) or R_(IV-4) must containV_(IV-1); R_(IV-5), R_(IV-6), R_(IV-7) and R_(IV-8) are eachindependently hydrogen, a bond, nitro or halo wherein said bond issubstituted with T_(IV) or a partially saturated, fully saturated orfully unsaturated (C₁-C₁₂) straight or branched carbon chain whereincarbon, may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(IV);

wherein T_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and

wherein R_(IV-5) and R_(IV-6), or R_(IV-6) and R_(IV-7), and/or R_(IV-7)and R_(IV-8) may also be taken together and can form at least one fourto eight membered ring that is partially saturated or fully unsaturatedoptionally having one to three heteroatoms independently selected fromnitrogen, sulfur and oxygen;

wherein said ring or rings formed by R_(IV-5) and R_(IV-6), or R_(IV-6)and R_(IV-7), and/or R_(IV-7) and R_(IV-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said (C₁-C₆)alkylsubstituent is also optionally substituted with from one to ninefluorines;

with the proviso that when R_(IV-2) is carboxyl or (C₁-C₄)alkylcarboxyl,then R_(IV-1) is not hydrogen.

Compounds of Formula IV and their methods of manufacture are disclosedin commonly assigned U.S. Pat. No. 6,197,786, U.S. application Ser. No.09/685,3000 filed Oct. 10, 2000 and PCT Publication No. WO00/17164, allof which are incorporated herein by reference in their entireties forall purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula IV:

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid tert -butyl ester;

[2R,4R] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinaline-1-carboxylic acid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy -ethyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester; and

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 4-aminosubstituted-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula V

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;

-   wherein R_(V-1) is Y_(V), W_(V)-X_(V) or W_(V)-Y_(V);-   wherein W_(V) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;-   X_(V) is -O—Y_(V), —S—Y_(V), —N(H)—Y_(V) or -N—(Y_(V))₂;

wherein Y_(V) for each occurrence is independently Z_(V) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(V);

wherein Z_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(V-2) is a partially saturated, fully saturated or fully unsaturatedone to six membered straight or branched carbon chain wherein thecarbons, other than the connecting carbon, may optionally be replacedwith one or two heteroatoms selected independently from oxygen, sulfurand nitrogen wherein said carbon atoms are optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(V-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(V-2) ring is optionally attached through (C₁-C₄)alkyl;

wherein said R_(V-2) ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

R_(V-3) is hydrogen or Q_(V);

wherein Q_(V) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(V);

wherein V_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(V) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N—(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(V-4) is cyano, formyl, W_(V-1)Q_(V-1), W_(V-1)V_(V-1),(C₁-C₄)alkyleneVvl or V_(V-2);

wherein W_(V-1) is carbonyl, thiocarbonyl, SO or SO₂,

wherein Q_(V-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons may optionally be replaced with one heteroatomselected from oxygen, sulfur and nitrogen and said carbon is optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono-, ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with V_(V-1);

wherein V_(V-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(V-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy, oxo, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein V_(V-2) is a partially saturated, fully saturated or fullyunsaturated five to seven membered ring containing one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(V-2) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₂)alkyl, (C₁-C₂)alkoxy,hydroxy, or oxo wherein said (C₁-C₂)alkyl optionally has from one tofive fluorines; and

wherein R_(V-4) does not include oxycarbonyl linked directly to the C⁴nitrogen;

wherein either R_(V-3) must contain V_(V) or R_(V-4) must containV_(V-1);

R_(V-5), R_(V-6), R_(V-7) and R_(V-8) are independently hydrogen, abond, nitro or halo wherein said bond is substituted with T_(V) or apartially saturated, fully saturated or fully unsaturated (C₁-C₂)straight or branched carbon chain wherein carbon may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(V);

wherein T_(V) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines;

wherein R_(V-5) and R_(V-6), or R_(V-6) and R_(V-7), and/or R_(V-7) andR_(V-8) may also be taken together and can form at least one ring thatis a partially saturated or fully unsaturated four to eight memberedring optionally having one to three heteroatoms independently selectedfrom nitrogen, sulfur and oxygen;

wherein said rings formed by R_(V-5) and R_(V-6), or R_(V-6) andR_(V-7), and/or R_(V-7) and R_(V-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C6)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines.

Compounds of Formula V and their methods of manufacture are disclosed incommonly assigned U.S. Pat. No. 6,140,343, U.S. patent application Ser.No 09/671,221 filed Sep. 27, 2000, and PCT Publication No. WO 00/17165,all of which are incorporated herein by reference in their entiretiesfor all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula V:

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2S,4S]4-[1-(3,5-bis-trifluoromethyl-benzyl)-ureido]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; and

[2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of cycloalkano-pyridines having the Formula VI

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;in which

A_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula -BNR_(VI-3)R_(VI-4), wherein

R_(VI-3) and R_(VI-4) are identical or different and denote a hydrogen,phenyl or a straight-chain or branched alkyl containing up to 6 carbonatoms,

D_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formulaR_(VI-5)-L_(VI)-,

or R_(VI-9)-T_(VI)-V_(VI)-X_(VI), wherein

R_(VI-5), R_(VI-6) and R_(VI-9) denote, independently from one another,a cycloalkyl containing 3 to 6 carbon atoms, or an aryl containing 6 to10 carbon atom or a 5- to 7-membered, optionally benzo-condensed,saturated or unsaturated, mono-, bi- or tricyclic heterocycle containingup to 4 heteroatoms from the series of S, N and/or O wherein the ringsare optionally substituted, in the case of the nitrogen-containing ringsalso via the N function, with up to five identical or differentsubstituents in the form of a halogen, trifluoromethyl, nitro, hydroxyl,cyano, carboxyl, trifluoromethoxy, a straight-chain or branched acyl,alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl containing up to6 carbon atoms each, an aryl or trifluoromethyl-substituted arylcontaining 6 to 10 carbon atoms each, or an optionally benzo-condensed,aromatic 5- to 7-membered heterocycle containing up to 3 heteoatoms fromthe series of S, N and/or O, and/or in the form of a group according tothe formula BOR_(VI-10), -SR_(VI-11), -SO₂R_(VI-12) orBNR_(VI-13)R_(VI-14), wherein

R_(VI-10), R_(VI-11), and R_(VI-12) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

R_(VI-13) and R_(VI-14) are identical or different and have the meaningof R_(VI-3) and R_(VI-4) given above, or

R_(VI-5) and/or R_(VI-6) denote a radical according to the formula

R_(VI-7) denotes a hydrogen or halogen, and

R_(VI-8) denotes a hydrogen, halogen, azido, trifluoromethyl, hydroxyl,trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula—NR_(VI-15)R_(VI-16),wherein

R_(VI-15) and R_(VI-16) are identical or different and have the meaningof R_(VI-3) and R_(VI-4) given above, or

R_(VI-7) and R_(VI-8) together form a radical according to the formula═O or ═NR_(VI-17), wherein

R_(VI-17) denotes a hydrogen or a straight-chain or branched alkyl,alkoxy or acyl containing up to 6 carbon atoms each,

L_(VI) denotes a straight-chain or branched alkylene or alkenylene chaincontaining up to 8 carbon atoms each, which are optionally substitutedwith up to two hydroxyl groups,

T_(VI) and X_(VI) are identical or different and denote a straight-chainor branched alkylene chain containing up to 8 carbon atoms, or

T_(VI) or X_(VI) denotes a bond,

V_(VI) denotes an oxygen or sulfur atom or an BNR_(VI-18) group, wherein

R_(VI-18) denotes a hydrogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms or a phenyl,

E_(VI) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl,

_(R) _(VI-1) and R_(VI-2) together form a straight-chain or branchedalkylene chain containing up to 7 carbon atoms, which must besubstituted with a carbonyl group and/or a radical according to theformula

wherein

a and b are identical or different and denote a number equaling 1, 2 or3,

_(RVI-19) denotes a hydrogen atom, a cycloalkyl containing 3 to 7 carbonatoms, a straight-chain or branched silylalkyl containing up to 8 carbonatoms, or a straight-chain or branched alkyl containing up to 8 carbonatoms, which is optionally substituted with a hydroxyl, a straight-chainor a branched alkoxy containing up to 6 carbon atoms or a phenyl, whichmay in turn be substituted with a halogen, nitro, trifluoromethyl,trifluoromethoxy or phenyl or tetrazole-substituted phenyl, and an alkylthat is optionally substituted with a group according to the formulaBOR_(VI-22), wherein

R_(VI-22) denotes a straight-chain or branched acyl containing up to 4carbon atoms or benzyl, or

R_(VI-19) denotes a straight-chain or branched acyl containing up to 20carbon atoms or benzoyl, which is optionally substituted with a halogen,trifluoromethyl, nitro or trifluoromethoxy, or a straight-chain orbranched fluoroacyl containing up to 8 carbon atoms,

R_(VI-20) and R_(VI-21) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms, or

R_(VI-20) and R_(VI-21) together form a 3- to 6-membered carbocyclicring, and a the carbocyclic rings formed are optionally substituted,optionally also geminally, with up to six identical or differentsubstituents in the form of trifluoromethyl, hydroxyl, nitrile, halogen,carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy containing 3to 7 carbon atoms each, a straight-chain or branched alkoxycarbonyl,alkoxy or alkylthio containing up to 6 carbon atoms each, or astraight-chain or branched alkyl containing up to 6 carbon atoms, whichis in turn substituted with up to two identical or differentsubstituents in the form of a hydroxyl, benzyloxy, trifluoromethyl,benzoyl, a straight-chain or branched alkoxy, oxyacyl or carboxylcontaining up to 4 carbon atoms each and/or a phenyl, which may in turnbe substituted with a halogen, trifluoromethyl or trifluoromethoxy,and/or the carbocyclic rings formed are optionally substituted, alsogeminally, with up to five identical or different substituents in theform of a phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turnare optionally substituted with a halogen, trifluoromethyl,trifluoromethoxy or nitro, and/or optionally in the form of a radicalaccording to the formula

wherein

c is a number equaling 1, 2, 3 or 4,

d is a number equaling 0 or 1,

R_(VI-23) and R_(VI-24) are identical or different and denote ahydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain orbranched alkyl containing up to 6 carbon atoms, benzyl or phenyl, whichis optionally substituted with up to two identical or differentsubstituents in the form of halogen, trifluoromethyl, cyano, phenyl ornitro, and/or the carbocyclic rings formed are optionally substitutedwith a spiro-linked radical according to the formula

wherein

W_(VI) denotes either an oxygen atom or a sulfur atom,

Y_(VI) and Y=_(VI) together form a 2- to 6-membered straight-chain orbranched alkylene chain,

e is a number equaling 1, 2, 3, 4, 5, 6 or 7,

f is a number equaling 1 or 2,

R_(VI-25), R_(VI-26), R_(VI-27), R_(VI-28), R_(VI-29), R_(VI-30) andR_(VI-31) are identical or different and denote a hydrogen,trifluoromethyl, phenyl, halogen or a straight-chain or branched alkylor alkoxy containing up to 6 carbon atoms each, or

R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each together denotea straight-chain or branched alkyl chain containing up to 6 carbon atomsor

R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each together form aradical according to the formula

wherein

W_(VI) has the meaning given above,

g is a number equaling 1, 2, 3, 4, 5, 6 or 7,

R_(VI-32) and R_(VI-33) together form a 3- to 7-membered heterocycle,which contains an oxygen or sulfur atom or a group according to theformula SO, SO₂ or BNR_(VI-34), wherein

R_(VI-34) denotes a hydrogen atom, a phenyl, benzyl, or a straight-chainor branched alkyl containing up to 4 carbon atoms, and salts and Noxides thereof, with the exception of 5(6H)-quinolones,3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

Compounds of Formula VI and their methods of manufacture are disclosedin European Patent Application No. EP 818448 A1, U.S. Pat. Nos.6,207,671 and 6,069,148, all of which are incorporated herein byreference in their entireties for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula VI:

2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one;

2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one;

[2-cyclopentyl-4-(4-fluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;

[5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;

[5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol;

5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline;and

2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroq uinolin-5-ol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted-pyridines having the Formula VII

or a pharmaceutically acceptable salt or tautomer thereof, wherein

R_(VII-2) and R_(VII-6) are independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinatedaralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that atleast one of R_(VII-2) and R_(VII-6) is fluorinated alkyl,chlorofluorinated alkyl or alkoxyalkyl;

R_(VII-3) is selected from the group consisting of hydroxy, amido,arylcarbonyl, heteroarylcarbonyl, hydroxymethyl —CHO, —CO₂R_(VII-7),wherein R_(VII-7) is selected from the group consisting of hydrogen,alkyl and cyanoalkyl; and

wherein R_(VII-15a) is selected from the group consisting of hydroxy,hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy,heteroaryloxy and heterocyclyloxy, and

R_(VII-16a) is selected from the group consisting of alkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, andheterocyclyl, arylalkoxy, trialkylsilyloxy;

R_(VII-4) is selected from the group consisting of hydrogen, hydroxy,halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl,hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy,alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy,alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio,alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio,cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkynylthioalkyl,alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl,heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl,alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl,heterocyclythioalkenyl, alkylamino, alkenylamino, alkynylamino,arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino,diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino,arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,—CO(O)N(R_(VII-8a)R_(VII-8b)), wherein R_(VII-8a) and R_(VII-8b) areindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl, —SO₂R_(VII-9), whereinR_(VII-9) is selected from the group consisting of hydroxy, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,—OP(O)(OR_(VII-10a)) (OR_(VII-10b)), wherein R_(VII-10a) and R_(VII-10b)are independently selected from the group consisting of hydrogen,hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and—OP(S) (OR_(VII-11a)) (OR_(VII-11b)), wherein R_(VII-11a) andR_(VII-11b) are independently selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

R_(VII-5) is selected from the group consisting of hydrogen, hydroxy,halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl,arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl,heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,alkoxyalkyl, alkenoxyalkyl, alkynoxylalkyl, aryloxyalkyl,heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl,alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl,heterocyclyloxyalkenyl, cyano, hydroxymethyl, —CO₂R_(VII-14), whereinR_(VII-14) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R_(VII-15b) is selected from the group consisting of hydroxy,hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy,heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and

R_(VII-16b) is selected form the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, andtrialkylsilyloxy;

wherein R_(VII-17) and R_(VII-18) are independently selected from thegroup consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl;

wherein R_(VII-19) is selected from the group consisting of alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,—SR_(VII-20), —OR_(VII-21), and BR_(VII-22)CO₂R_(VII-23), wherein

R_(VII-20) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl,alkylheteroarylamino, arylheteroarylamino,

R_(VII-21) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl,

R_(VII-22) is selected from the group consisting of alkylene or arylene,and

R_(VII-23) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R_(VII-124) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, aralkenyl, and aralkynyl;

wherein R_(VII-25) is heterocyclylidenyl;

wherein R_(VII-26) and R_(VII-27) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-28) and R_(VII-29) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-30) and R_(VII-31) are independently alkoxy, alkenoxy,alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

wherein R_(VII-32) and R_(VII-33) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-36) is selected from the group consisting of alkyl,alkenyl, aryl, heteroaryl and heterocyclyl;

wherein R_(VI-37) and R_(VII-38) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-39) is selected from the group consisting of hydrogen,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio andheterocyclylthio, and

R_(VII-40) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy,heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio;—N═R_(VII-41),

wherein R_(VII-41) is heterocyclylidenyl;

wherein R_(VII-42) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and

R_(VII-43) is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl,haloheteroaryl, and haloheterocyclyl;

wherein R_(VII-44) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;—N═S=O;—N═C=S;—N═C=O;—N₃;—SR_(VII-45)

wherein R_(VII-45) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl,heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl,heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl,aminocarbonylaryl, aminocarbonylheteroaryl, andaminocarbonylheterocyclyl,—SR_(VII-46), and —CH₂R_(VII-47),

wherein R_(VII-46) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R_(VII-47) is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

wherein R_(VII-48) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,and

R_(VII-49) is selected from the group consisting of alkoxy, alkenoxy,alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

wherein R_(VII-50) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy;

wherein R_(VII-51) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;and

wherein R_(VII-53) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

provided that when R_(VII-5) is selected from the group consisting ofheterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl radical ofthe corresponding heterocyclylalkyl or heterocyclylalkenyl is other thanδ-lactone; and

provided that when R_(VII-4) is aryl, heteroaryl or heterocyclyl, andone of R_(VII-2) and R_(VII-6) is trifluoromethyl, then the other ofR_(VII-2) and R_(VII-6) is difluoromethyl.

Compounds of Formula VII and their methods of manufacture are disclosedin PCT Publication No. WO 9941237-A1, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor of Formula VII is dimethyl5,5-dithiobis[2-difluoromethyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted biphenyls having the Formula VIII

or a pharmaceutically acceptable salt, enantiomers, or stereoisomersthereof, in which

A_(VIII) stands for aryl with 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times in an identical manner or differently byhalogen, hydroxy, trifluoromethyl, trifluoromethoxy, or bystraight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

-   -   —NR_(VIII-1), R_(VIII-2), wherein

R_(VIII-1) and R_(VIII-2) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms,

D_(VIII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, which is substituted by hydroxy,

E_(VIII) and L_(VIII) are either identical or different and stand forstraight-chain or branched alkyl with up to 8 carbon atoms, which isoptionally substituted by cycloalkyl with 3 to 8 carbon atoms, or standsfor cycloalkyl with 3 to 8 carbon atoms, or

E_(VIII) has the above-mentioned meaning and

L_(VIII) in this case stands for aryl with 6 to 10 carbon atoms, whichis optionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula—NR_(VIII-3)R_(VIII-4), wherein

R_(VIII-3) and R_(VIII-4) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

E_(VIII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, or stands for aryl with 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times in an identical manner or differently byhalogen, hydroxy, trifluoromethyl, trifluoromethoxy, or bystraight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula—NR_(VIII-5)R_(VIII-6), wherein

R_(VIII-5) and R_(VII-6) are identical or different and have the meaninggiven above for R_(VIII-1) and R_(VIII-2), and

L_(VIII) in this case stands for straight-chain or branched alkoxy withup to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms,

T_(VIII) stands for a radical of the formula

R_(VIII-7) and R_(VIII-8) are identical or different and denotecycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or denote a 5- to 7-member aromatic, optionally benzo-condensed,heterocyclic compound with up to 3 heteroatoms from the series S, Nand/or O, which are optionally substituted up to 3 times in an identicalmanner or differently by trifluoromethyl, trifluoromethoxy, halogen,hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, oralkoxycarbonyl with up to 6 carbon atoms each, or by -phenyl, phenoxy,or thiophenyl, which can in turn be substituted by halogen,trifluoromethyl, or trifluoromethoxy, and/or the rings are substitutedby a group of the formula—NR_(VIII-11)R_(VIII-2), wherein

R_(VIII-11) and R_(VIII-12) are identical or different and have themeaning given above for Rv_(VIII-1) and R_(VIII-2),

X_(VIII) denotes a straight or branched alkyl chain or alkenyl chainwith 2 to carbon atoms each, which are optionally substituted up to 2times by hydroxy,

R_(VIII-9) denotes hydrogen, and

R_(VIII-10) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to5 carbon atoms, or a radical of the formula—NR_(VIII-13)R_(VIII-14), wherein

R_(VIII-13) and R_(VIII-14) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

R_(VIII-9) and R_(VIII-10) form a carbonyl group together with thecarbon atom.

Compounds of Formula VIII are disclosed in PCT Publication No. WO9804528, which is incorporated herein by reference in its entirety forall purposes.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted 1,2,4-triazoles having the Formula IX

or a pharmaceutically acceptable salt or tautomer thereof;

wherein R_(IX-1) is selected from higher alkyl, higher alkenyl, higheralkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl,arylthioalkyl, and cycloalkylalkyl;

wherein R_(IX-2) is selected from aryl, heteroaryl, cycloalkyl, andcycloalkenyl, wherein

R_(IX-2) is optionally substituted at a substitutable position with oneor more radicals independently selected from alkyl, haloalkyl,alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy,aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino anddialkylamino; and

wherein R_(IX-3) is selected from hydrido, —SH and halo;

provided R_(IX-2) cannot be phenyl or 4-methylphenyl when R_(IX-1) ishigher alkyl and when R_(IX-3) is BSH.

Compounds of Formula IX and their methods of manufacture are disclosedin PCT Publication No. WO 9914204, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula IX:

2,4-dihydro-4-(3-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(2-fluorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(2-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(3-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(2-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(3-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

4-cyclohexyl-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(3-pyridyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(2-ethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(2,6-dimethylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(4-phenoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

4-(1,3-benzodioxol-5-yl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

4-(2-chlorophenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(4-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-5-tridecyl-4-(3-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;

2,4-dihydro-5-tridecyl-4-(3-fluorophenyl)-3H-1,2,4-triazole-3-thione;

4-(3-chloro-4-methylphenyl)-2.4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(2-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

4-(4-benzyloxyphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(2-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-5-tridecyl-4-(4-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(1-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(3-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(4-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(3,4-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(2,5-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(2-methoxy-5-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

4-(4-aminosulfonylphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-5-dodecyl-4-(3-methoxyphenyl)-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(3-methoxyphenyl)-5-tetradecyl-3H-1,2,4-triazole-3-thione;

2,4-dihydro-4-(3-methoxyphenyl)-5-undecyl-3H-1,2,4-triazole-3-thione;and

2,4-dihydro-(4-methoxyphenyl)-5-pentadecyl-3H-1,2,4-triazole-3-thione.

Another class of CETP inhibitors that finds utility with the presentinvention consists of hetero-tetrahydroquinolines having the Formula X

and pharmaceutically acceptable salts, enantiomers, or stereoisomers orN-oxides of said compounds;in which

A_(X) represents cycloalkyl with 3 to 8 carbon atoms or a 5 to7-membered, saturated, partially saturated or unsaturated, optionallybenzo-condensed heterocyclic ring containing up to 3 heteroatoms fromthe series comprising S, N and/or O, that in case of a saturatedheterocyclic ring is bonded to a nitrogen function, optionally bridgedover it, and in which the aromatic systems mentioned above areoptionally substituted up to 5-times in an identical or differentsubstituents in the form of halogen, nitro, hydroxy, trifluoromethyl,trifluoromethoxy or by a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group ofthe formula BNR_(X-3)R_(X-4),

in which

R_(X-3) and R_(X-4) are identical or different and denote hydrogen,phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

or

A_(X) represents a radical of the formula

D_(X) represents an aryl having 6 to 10 carbon atoms, that is optionallysubstituted by phenyl, nitro, halogen, trifluormethyl ortrifluormethoxy, or it represents a radical of the formula

in which

R_(X-5), R_(X-6) and R_(X-9) independently of one another denotecycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbonatoms or a 5- to 7-membered aromatic, optionally benzo-condensedsaturated or unsaturated, mono-, bi-, or tricyclic heterocyclic ringwherein the heteroatoms are selected from the series consisting of S, Nand/or O, in which the rings are substituted, optionally, in case of thenitrogen containing aromatic rings via the N function, with up to 5identical or different substituents in the form of halogen,trifluoromethyl, nitro, hydroxy, cyano, carbonyl, trifluoromethoxy,straight straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy,alkoxy, or alkoxycarbonyl each having up to 6 carbon atoms, by aryl ortrifluoromethyl-substituted aryl each having 6 to 10 carbon atoms or byan, optionally benzo-condensed, aromatic 5- to 7-membered heterocyclicring having up to 3 heteroatoms from the series consisting of S, N,and/or O, and/or substituted by a group of the formula BOR_(X-10),—SR_(X-11), SO₂R_(X-12) or BNR_(X-13)R_(X-14),

in which

R_(X-10), R_(X-11) and R_(X-12) independently from each other denotearyl having 6 to 10 carbon atoms, which is in turn substituted with upto 2 identical or different substituents in the form of phenyl, halogenor a straight-chain or branched alkyl having up to 6 carbon atoms,

R_(X-13) and R_(X-14) are identical or different and have the meaning ofR_(X-3) and R_(X-4) indicated above,

or

R_(X-5) and/or R_(X-6) denote a radical of the formula

R_(X-7) denotes hydrogen or halogen, and

R_(X-8) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,trifluoromethoxy, straight-chain or branched alkoxy or alkyl having upto 6 carbon atoms or a radical of the formula

BNR_(X-15)R_(X-16),

in which

R_(X-15) and R_(X-16) are identical or different and have the meaning ofR_(X-3) and R_(X-4) indicated above,

or

R_(X-7) and R_(X-8) together form a radical of the formula ═O or═NR_(X-17), in which

R_(X-17) denotes hydrogen or straight chain or branched alkyl, alkoxy oracyl having up to 6 carbon atoms,

L_(X) denotes a straight chain or branched alkylene or alkenylene chainhaving up to 8 carbon atoms, that are optionally substituted with up to2 hydroxy groups,

T_(X) and X_(X) are identical or different and denote a straight chainor branched alkylene chain with up to 8 carbon atoms

or

T_(X) or X_(X) denotes a bond,

V_(X) represents an oxygen or sulfur atom or an BNR_(X-18)-group, inwhich

R_(X-18) denotes hydrogen or straight chain or branched alkyl with up to6 carbon atoms or phenyl,

E_(X) represents cycloalkyl with 3 to 8 carbon atoms, or straight chainor branched alkyl with up to 8 carbon atoms, that is optionallysubstituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, orrepresents a phenyl, that is optionally substituted by halogen ortrifluoromethyl,

R_(X-1) and R_(X-2) together form a straight-chain or branched alkylenechain with up to 7 carbon atoms, that must be substituted by carbonylgroup and/or by a radical with the formula

in which a and b are identical or different and denote a number equaling1, 2, or 3,

R_(X-19) denotes hydrogen, cycloalkyl with 3 up to 7 carbon atoms,straight chain or branched silylalkyl with up to 8 carbon atoms orstraight chain or branched alkyl with up to 8 carbon atoms, that areoptionally substituted by hydroxyl, straight chain or branched alkoxywith up to 6 carbon atoms or by phenyl, which in turn might besubstituted by halogen, nitro, trifluormethyl, trifluoromethoxy or byphenyl or by tetrazole-substituted phenyl, and alkyl, optionally besubstituted by a group with the formula BOR_(X-22),

in which

R_(X-22) denotes a straight chain or branched acyl with up to 4 carbonatoms or benzyl,

or

R_(X-19) denotes straight chain or branched acyl with up to 20 carbonatoms or benzoyl, that is optionally substituted by halogen ,trifluoromethyl, nitro or trifluoromethoxy, or it denotes straight chainor branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

R_(X-20) and R_(X-21) are identical or different and denote hydrogen,phenyl or straight chain or branched alkyl with up to 6 carbon atoms,

or

R_(X-20) and R_(X-21) together form a 3- to 6- membered carbocyclicring, and the carbocyclic rings formed are optionally substituted,optionally also geminally, with up to six identical or differentsubstituents in the form of triflouromethyl, hydroxy, nitrile, halogen,carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7carbon atoms each, by straight chain or branched alkoxycarbonyl, alkoxyor alkylthio with up to 6 carbon atoms each or by straight chain orbranched alkyl with up to 6 carbon atoms, which in turn is substitutedwith up to 2 identically or differently by hydroxyl, benzyloxy,trifluoromethyl, benzoyl, straight chain or branched alkoxy, oxyacyl orcarbonyl with up to 4 carbon atoms each and/or phenyl, which may in turnbe substituted with a halogen, trifuoromethyl or trifluoromethoxy,and/or the formed carbocyclic rings are optionally substituted, alsogeminally, with up to 5 identical or different substituents in the formof phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn areoptionally substituted by halogen, trifluoromethyl, trifluoromethoxy ornitro, and/or optionally are substituted by a radical with the formula

in which

c denotes a number equaling 1, 2, 3, or 4,

d denotes a number equaling 0 or 1,

R_(X-23) and R_(X-24) are identical or different and denote hydrogen,cycloalkyl with 3 to 6 carbon atoms, straight chain or branched alkylwith up to 6 carbon atoms, benzyl or phenyl, that is optionallysubstituted with up to 2 identically or differently by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the formed carbocyclicrings are substituted optionally by a spiro-linked radical with theformula

in which

W_(X) denotes either an oxygen or a sulfur atom

Y_(X) and Y′_(X) together form a 2 to 6 membered straight chain orbranched alkylene chain,

-   e denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,-   f denotes a number equaling 1 or 2,

R_(X-25), R_(X-26), R_(X-27), R_(X-28), R_(X-29), R_(X-30) and R_(X-31)are identical or different and denote hydrogen, trifluoromethyl, phenyl,halogen or straight chain or branched alkyl or alkoxy with up to 6carbon atoms each,

or

R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) respectively formtogether a straight chain or branched alkyl chain with up to 6 carbonatoms,

or

R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) each together form aradical with the formula

in which

W_(X) has the meaning given above,

-   g denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

R_(X-32) and R_(X-33) form/together a 3- to 7- membered heterocycle,which contains an oxygen or sulfur atom or a group with the formula SO,SO₂ or —NR_(X-34),

in which

R_(X-34) denotes hydrogen, phenyl, benzyl or straight or branched alkylwith up to 4 carbon atoms.

Compounds of Formula X and their methods of manufacture are disclosed inPCT Publication No. WO 9914215, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula X:

2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenxoyl)-5,6,7,8-tetrahydroquinoline;

2-cyclopentyl-3-[fluoro-(4-trifluoromethylphenyl)methyl]-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline;and

2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(trifluoromethylbenxyl)-5,6,7,8-tetrahydroquinoline.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted tetrahydro naphthalines and analogouscompound having the Formula XI

and stereoisomers, stereoisomer mixtures, and salts thereof, in whichA_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or stands foraryl with 6 to 10 carbon atoms, or stands for a 5- to 7-membered,saturated, partially unsaturated or unsaturated, possiblybenzocondensated, heterocycle with up to 4 heteroatoms from the seriesS, N and/or O, where aryl and the heterocyclic ring systems mentionedabove are substituted up to 5-fold, identical or different, by cyano,halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluorl-methoxy,or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio,alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbonatoms, or by a group of the formula—NR_(XI-3)R_(XI-4),in which

R_(XI-3) and R_(XI-4) are identical or different and denote hydrogen,phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms

D_(XI) stands for a radical of the formula

in which

R_(XI-5), R_(XI-6) and R_(XI-9), independent of each other, denotecycloalkyl with 3 to 6 carbon atoms, or denote aryl with 6 to 10 carbonatoms, or denote a 5- to 7-membered, possibly benzocondensated,saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to4 heteroatoms of the series S, N and/or O, where the cycles are possiblysubstituted in the case of the nitrogen-containing rings also via theN-functionCup to 5-fold, identical or different, by halogen,trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy,straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl with up to 6 carbon atoms each, by aryl ortrifluoromethyl substituted aryl with 6 to 10 carbon atoms each, or by apossibly benzocondensated aromatic 5- to 7-membered heterocycle with upto 3 heteroatoms of the series S, N and/or O, and/or are substituted bya group of the formula

—OR_(XI-10), —SR_(XI-11), —SO₂R_(XI-12) or —NR_(XI-13)R_(XI-14),

in which

R_(XI-10), R_(XI-11) and R_(XI-12), independent of each other, denotearyl with 6 to 10 carbon atoms, which itself is substituted up to2-fold, identical or different, by phenyl, halogen. or by straight-chainor branched alkyl with up to 6 carbon atoms,

R_(XI-13) and R_(XI-14) are identical or different and have the meaninggiven above for R_(XI-3) and R_(XI-4),

or

R_(XI-5) and/or R_(XI-6) denote a radical of the formula

R_(XI-7) denotes hydrogen, halogen or methyl,

and

R_(XI-8) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,trifluoromethoxy, straight-chain or branched alkoxy or alkyl with up to6 carbon atoms each, or a radical of the formula —NR_(XI-15)R_(XI-16),

in which

R_(XI-15) and R_(XI-16) are identical or different and have the meaninggiven above for R_(XI-3) and R_(XI-4),

or

R_(XI-17) and R_(XI-8) together form a radical of the formula ═O or═NR_(XI-17), in which

R_(XI-17) denotes hydrogen or straight-chain or branched alkyl, alkoxyor acyl with up to 6 carbon atoms each,

L_(XI) denotes a straight-chain or branched alkylene- or alkenylenechain with up to 8 carbon atoms each, which is possibly substituted upto 2-fold by hydroxy,

T_(XI) and X_(XI) are identical or different and denote a straight-chainor branched alkylene chain with up to 8 carbon atoms,

or

T_(XI) and X_(XI) denotes a bond,

V_(XI) stands for an oxygen- or sulfur atom or for an —NR_(XI-18) group,

in which

R_(XI-18) denotes hydrogen or straight-chain or branched alkyl with upto 6 carbon atoms, or phenyl,

E_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or stands forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy,or stands for phenyl, which is possibly substituted by halogen ortrifluoromethyl,

R_(XI-1) and R_(XI-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, which must be substituted by acarbonyl group and/or by a radical of the formula

in which

a and b are identical or different and denote a number 1, 2 or 3

R_(XI-19) denotes hydrogen, cycloalkyl with 3 to 7 carbon atoms,straight-chain or branched silylalkyl with up to 8 carbon atoms, orstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by hydroxy, straight-chain or branched alkoxy withup to 6 carbon atoms, or by phenyl, which itself can be substituted byhalogen, nitro, trifluoromethyl, trifluoromethoxy or by phenylsubstituted by phenyl or tetrazol, and alkyl is possibly substituted bya group of the formula —OR_(XI-22),

in which

R_(XI-22) denotes straight-chain or branched acyl with up to 4 carbonatoms, or benzyl,

or

R_(XI-19) denotes straight-chain or branched acyl with up to 20 carbonatoms or benzoyl, which is possibly substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain orbranched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

R_(XI-20) and R_(XI-21) are identical or different, denoting hydrogen,phenyl or straight-chain or branched alkyl with up to 6 carbon atoms,

or

R_(XI-20) and R_(XI-21) together form a 3- to 6-membered carbocycle,and, possibly also geminally, the alkylene chain formed by R_(XI-1) andR_(XI-2), is possibly substituted up to 6-fold, identical or different,by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido,cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each, bystraight-chain or branched alkoxycarbonyl, alkoxy or alkoxythio with upto 6 carbon atoms each, or by straight- chain or branched alkyl with upto 6 carbon atoms, which itself is substituted up to 2-fold, identicalor different. by hydroxyl, benzyloxy, trifluoromethyl, benzoyl,straight-chain or branched alkoxy, oxyacyl or carboxyl with up to 4carbon atoms each, and/or phenyl- which itself can be substituted byhalogen, trifluoromethyl or trifluoromethoxy, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is substituted, also geminally, possiblyup to 5-fold, identical or different, by phenyl, benzoyl, thiophenyl orsulfobenzyl -which themselves are possibly substituted by halogen,trifluoromethyl, trifluoromethoxy or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by a radical ofthe formula

in which

c denotes a number 1, 2, 3 or 4,

d denotes a number 0 or 1,

R_(XI-23) and R_(XI-24) are identical or different and denote hydrogen,cycloalkyl with 3 to 6 carbon atoms, straight-chain or branched alkylwith up to 6 carbon atoms, benzyl or phenyl, which is possiblysubstituted up to 2-fold. identical or different, by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by aspiro-jointed radical of the formula

in which

W_(XI) denotes either an oxygen or a sulfur atom,

Y_(XI) and Y′_(XI) together form a 2- to 6-membered straight-chain orbranched alkylene chain,

e is a number 1, 2, 3, 4, 5, 6 or 7,

f denotes a number 1 or 2,

R_(XI-25), R_(XI-26), R_(XI-27), R_(XI-28), R_(XI-29), R_(XI-30) andR_(XI-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

or

R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together form astraight-chain or branched alkyl chain with up to 6 carbon atoms,

or

R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together form aradical of the formula

in which

W_(XI) has the meaning given above,

g is a number 1, 2, 3, 4, 5, 6 or 7,

R_(XI-32) and R_(XI-33) together form a 3- to 7-membered heterocyclethat contains an oxygen- or sulfur atom or a group of the formula SO,SO₂ or —NR_(XI-34),

in which

R_(XI-34) denotes hydrogen, phenyl, benzyl, or straight-chain orbranched alkyl with up to 4 carbon atoms.

Compounds of Formula XI and their methods of manufacture are disclosedin PCT Publication No. WO 9914174, which is incorporated herein byreference in its entirety for all purposes.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 2-aryl-substituted pyridines having the Formula(XII)

or pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds,in which

A_(XII) and E_(XII) are identical or different and stand for aryl with 6to 10 carbon atoms which is possibly substituted, up to 5-fold identicalor different, by halogen, hydroxy, trifluoromethyl, trifluoromethoxy,nitro or by straight-chain or branched alkyl, acyl, hydroxy alkyl oralkoxy with up to 7 carbon atoms each, or by a group of the formula—NR_(XII-1)R_(XII-2),

where

R_(XII-1) and R_(XII-2) are identical or different and are meant to behydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbonatoms,

D_(XII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, which is substituted by hydroxy,

L_(XII) stands for cycloalkyl with 3 to 8 carbon atoms or forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms, or byhydroxy,

T_(XII) stands for a radical of the formula R_(XII-3)—X_(XII)- or

where

R_(XII-3) and R_(XII-4) are identical or different and are meant to becycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or a 5- to 7-membered aromatic, possibly benzocondensated heterocyclewith up to 3 heteroatoms from the series S, N and/or O, which arepossibly substituted up to 3-fold identical or different, bytrifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, bystraight-chain or branched alkyl acyl, alkoxy or alkoxycarbonyl with upto 6 carbon atoms each or by phenyl, phenoxy or phenylthio which in turncan be substituted by halogen trifluoromethyl or trifluoromethoxy,and/or where the cycles are possibly substituted by a group of theformula —NR_(XII-7)R_(XII-8),

where

R_(XII-7) and R_(XII-8) are identical or different and have the meaningof R_(XII-1) and R_(XII-2) given above,

X_(XII) is a straight-chain or branched alkyl or alkenyl with 2 to 10carbon atoms each, possibly substituted up to 2-fold by hydroxy orhalogen,

R_(XII-5) stands for hydrogen,

and

R_(XII-6) means to be hydrogen, halogen, mercapto, azido,trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branchedalkoxy with up to 5 carbon atoms, or a radical of the formulaBNR_(XII-9)R_(XII-10),

where

R_(XII-9) and R_(XII-10) are identical or different and have the meaningof R_(XII-1) and R_(XII-2) given above, or

R_(XII-5) and R_(XII-6), together with the carbon atom, form a carbonylgroup.

Compounds of Formula XII and their methods of manufacture are disclosedin EP 796846-A1, U.S. Pat. No. 6,127,383 and U.S. Pat. No. 5,925,645,all of which are incorporated herein by reference in their entiretiesfor all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XII:

4,6-bis-(p-fluorophenyl)-2-isopropyl-3-[(p-trifluoromethylphenyl)-(fluoro)methyl]-5-(1-hydroxyethyl)pyridine;

2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[4-(trifluoromethylphenyl)fluoromethyl]-3-hydroxymethyl)pyridine;and

2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[2-(3-trifluoromethylphenyl)vinyl]-3-hydroxymethyl)pyridine.

Another class of CETP inhibitors that finds utility with the presentinvention consists of compounds having the Formula (XIII)

or pharmaceutically acceptable salts, enantiomers, stereoisomers,hydrates, or solvates of said compounds, in which

R_(XIII) is a straight chain or branched C_(I-10) alkyl; straight chainor branched C₂₋₁₀ alkenyl; halogenated C_(I-4) lower alkyl; C₃₋₁₀cycloalkyl that may be substituted; C₅₋₈ cycloalkenyl that may besubstituted; C₃₋₁₀ cycloalkyl C_(I-10) alkyl that may be substituted;aryl that may be substituted; aralkyl that may be substituted; or a 5-or 6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygenatoms or sulfur atoms that may be substituted,

X_(XIII-1), X_(XIII-2), X_(XIII-3), X_(XIII-4) may be the same ordifferent and are a hydrogen atom; halogen atom; C_(I-4) lower alkyl;halogenated C_(I-4) lower alkyl; C_(I-4) lower alkoxy; cyano group;nitro group; acyl; or aryl, respectively;

Y_(XIII) is —CO—; or BSO₂—; and

Z_(XIII) is a hydrogen atom; or mercapto protective group.

Compounds of Formula XIII and their methods of manufacture are disclosedin PCT Publication No. WO 98/35937, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XIII;

N,N′-(dithiodi-2,1-phenylene)bis[2,2-dimethyl-propanamide];

N,N′-(dithiodi-2,1-phenylene)bis[1-methyl-cyclohexanecarboxamide];

N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)cyclopentanecarboxamide];

N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)cyclohexanecarboxamide];

N,N′-(dithiodi-2,1-phenylene)bis[1-(2-ethylbutyl)cyclohexanecarboxamide];

N,N′-(dithiodi-2,1-phenylene)bis-tricyclo[3.3.1.1^(3.7)]decane-1-carboxamide;

propanethioic acid,2-methyl-,S-[2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester;

propanethioic acid,2,2-dimethyl-,S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester;and

ethanethioic acid,S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of polycyclicaryl and heteroaryltertiary-heteroalkylamines having the Formula XIV

and pharmaceutically acceptable forms thereof, wherein:

n_(XIV) is an integer selected from 0 through 5;

R_(XIV-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

X_(XIV) is selected from the group consisting of O, H, F, S, S(O), NH,N(OH), N(alkyl), and N(alkoxy);

R_(XIV-16) is selected from the group consisting of hydrido, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl,monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl,dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl,heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacerselected from the group consisting of a covalent single bond and alinear spacer moiety having from 1 through 4 contiguous atoms linked tothe point of bonding of an aromatic substituent selected from the groupconsisting of R_(XIV-4), R_(XIV-8), R_(XIV-9), and R_(XIV-13) to form aheterocyclyl ring having from 5 through 10 contiguous members with theprovisos that said spacer moiety is other than a covalent single bondwhen R_(XIV-2) is alkyl and there is no R_(XIV-16) wherein X is H or F;

D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) is a covalent bond, nomore than one of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) andK_(XIV-1) is O, no more than one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) is S, one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) must be a covalent bond when two of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) are O and S, and no morethan four of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1)are N;

D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) is a covalent bond, nomore than one of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) andK_(XIV-2) is O, no more than one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) is S, one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) must be a covalent bond when two of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) are O and S, and no morethan four of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2)and K_(XIV-2) are N;

R_(XIV-2) is independently selected from the group consisting ofhydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino,dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,aloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl,haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl,arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl,cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl,cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

R_(XIV-2) and R_(XIV-3) are taken together to form a linear spacermoiety selected from the group consisting of a covalent single bond anda moiety having from 1 through 6 contiguous atoms to form a ringselected from the group consisting of a cycloalkyl having from 3 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, and a heterocyclyl having from 4 through 8 contiguous members;

R_(XIV-3) is selected from the group consisting of hydrido, hydroxy,halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino,acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl,heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl,alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl,aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl,cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

Y_(XIV) is selected from a group consisting of a covalent singlebond,(C(R_(XIV-14))₂)_(qXIV) wherein _(qXIV) is an integer selected from1 and 2 and (CH(R_(XIV-14)))_(gXIV)—W_(XIV)—(CH(R_(XIV-14)))_(pXIV)wherein _(gXIV) and _(pXIV) are integers independently selected from 0and 1;

R_(XIV-14) is independently selected from the group consisting ofhydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a heterocyclyl having from 5 through 8 contiguous members with theproviso that, when Y_(XIV) is a covalent bond, an R_(XIV-14) substituentis not attached to Y_(XIV);

R_(XIV-14) and R_(XIV-14), when bonded to the different atoms, are takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

R_(XIV-14) and R_(XIV-14), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

W_(XIV) is selected from the group consisting of O, C(O), C(S),C(O)N(R_(XIV-14)), C(S)N(R_(XIV-14)), (R_(XIV-14))NC(O),(R_(XIV-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XIV-14)),(R_(XIV-14))NS(O)₂, and N(R_(XIV-14)) with the proviso that R_(XIV-14)is selected from other than halo and cyano;

Z_(XIV) is independently selected from a group consisting of a covalentsingle bond, (C(R_(XIV-15))₂)_(qXIV-2) wherein _(qXIV-2) is an integerselected from 1 and 2, (CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV)wherein _(jXIV) and _(kXIV) are integers independently selected from 0and 1 with the proviso that, when Z_(XIV) is a covalent single bond, anR_(XIV-15) substituent is not attached to Z_(XIV);

R_(XIV-15) is independently selected, when Z_(XIV) is(C(R_(XIV-15))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2, from the group consisting of hydrido, hydroxy, halo, cyano,aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl,heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members, and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a heterocyclyl having from 5 through 8 contiguous members;

R_(XIV-15) and R_(XIV-15), when bonded to the different atoms, are takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

R_(XIV-15) and R_(XIV-15), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

R_(XIV-15) is independently selected, when Z_(XIV) is(CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1, from the groupconsisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl,heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma linear moiety having a chain length of 3 to 6 atoms connected to thepoint of bonding selected from the group consisting of R_(XIV-4) andR_(XIV-8) to form a ring selected from the group consisting ofa,cycloalkenyl ring having from through 8 contiguous members and aheterocyclyl ring having from 5 through 8 contiguous members, and aspacer selected from a linear moiety having a chain length of 2 to 5atoms connected to the point of bonding selected from the groupconsisting of R_(XIV-9) and R_(XIV-13) to form a heterocyclyl ringhaving from 5 through 8 contiguous members;

R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7), R_(XIV-8), R_(XIV-9),R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13) are independentlyselected from the group consisting of perhaloaryloxy, alkanoylalkyl,alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido,N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl,cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl,dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl; haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that there are one to fivenon-hydrido ring substituents R_(XIV-4), R_(XIV-5), R_(XIV-6),R_(XIV-7), and R_(XIV-8) present, that there are one to five non-hydridoring substituents R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), andR_(XIV-13) present, and R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7),R_(XIV-8), R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13)are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

R_(XIV-4) and R_(XIV-5), R_(XIV-5) and R_(XIV-6), R_(XIV-6) andR_(XIV-7), R_(XIV-7) and R_(XIV-8), R_(XIV-8) and R_(XIV-9), R_(XIV-9)and R_(XIV-10), R_(XIV-10) and R_(XIV-11), R_(XIV-11) and R_(XIV-12),and R_(XIV-12) and R_(XIV-13) are independently selected to form spacerpairs wherein a spacer pair is taken together to form a linear moietyhaving from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R_(XIV-4) and R_(XIV-5), R_(XIV-5) andR_(XIV-6), R_(XIV-6) and R_(XIV-)7, and R_(XIV-7) and R_(XIV-8) are usedat the same time and that no more than one of the group consisting ofspacer pairs R_(XIV-9) and R_(XIV-10), R_(XIV-10) and R_(XIV-11),R_(XIV-11) and R_(XIV-12), and R_(XIV-12) and R_(XIV-13) are used at thesame time;

R_(XIV-4) and R_(XIV-9), R_(XIV-4) and R_(XIV-13), R_(XIV-8) andR_(XIV-9) and R_(XIV-8) and R_(XIV-13) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XIV-4) and R_(XIV-9), R_(XIV-4)and R_(XIV-13), R_(XIV-8) and R_(XIV-9), and R_(XIV-8) and R_(XIV-13) isused at the same time.

Compounds of Formula XIV and their methods of manufacture are disclosedin PCT Publication No. WO 00/18721, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XIV:

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-methlylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;

3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]methoxy]phenyl]amino]-1,1,-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethymethyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-methylphenoxy)phenyl][[3-pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptaflubropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1-trifluoro-2-propanol;

3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-4-(trifluoromethylphenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and

3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines having the Formula XV

and pharmaceutically acceptable forms thereof, wherein:

n_(XV) is an integer selected from 1 through 2;

A_(XV) and Q_(XV) are independently selected from the group consistingof—CH₂(CR_(XV-37)R_(XV-38))_(vXV)—(CR_(XV-33)R_(XV-34))_(uXV)—T_(XV)—(CR_(XV-35)R_(XV-36))_(wXV)—H,

with the provisos that one of A_(XV) and Q_(XV) must be AQ-1 and thatone of A_(XV) and Q_(XV) must be selected from the group consisting ofAQ-2 and—CH₂(CR_(XV-37)R_(XV-38))_(vXV)—(CR_(XV-33)R_(XV-34))_(uXV)—T_(XV)—(CR_(XV-35)R_(XV-36))_(wXV)—H;

T_(XV) is selected from the group consisting of a single covalent bond,O, S, S(O), S(O)₂, C(R_(XV-33))═C(R_(XV-35)), and C≡C;

_(vXV) is an integer selected from 0 through 1 with the proviso that_(vXV) is 1 when any one of R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) is aryl or heteroaryl;

_(uXV) and _(wXV) are integers independently selected from 0 through 6;

A_(XV-1) is C(R_(XV-30));

D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) are independentlyselected from the group consisting of C, N, O, S and a covalent bondwith the provisos that no more than one of D_(XV-1), D_(XV-2), J_(XV-1),J_(XV-2), and K_(XV-1) is a covalent bond, no more than one of D_(XV-1),D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is O, no more than one ofD_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is S, one ofD_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) must be a covalentbond when two of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1)are O and S, and no more than four of D_(XV-1), D_(XV-2), J_(XV-1),J_(XV-2), and K_(XV-1) are N;

B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are independently selected from the group consisting of C, C(R_(XV-30)),N, O, S and a covalent bond with the provisos that no more than 5 ofB_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are a covalent bond, no more than two of B_(XV-1), B_(XV-2), D_(XV-3),D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are O, no more than two ofB_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are S, no more than two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4),J_(XV-3), J_(XV-4), and K_(XV-2) are simultaneously O and S, and no morethan two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4),and K_(XV-2) are N;

B_(XV-1) and D_(XV-3), D_(XV-3) and J_(XV-3), J_(XV-3) and K_(XV-2),K_(XV-2) and J_(XV-4), J_(XV-4) and D_(XV-4), and D_(XV-4) and B_(XV-2)are independently selected to form an in-ring spacer pair wherein saidspacer pair is selected from the group consisting ofC(R_(XV-33))═C(R_(XV-35)) and N═N with the provisos that AQ-2 must be aring of at least five contiguous members, that no more than two of thegroup of said spacer pairs are simultaneously C(R_(XV-33))═C(R_(XV-35))and that no more than one of the group of said spacer pairs can be N═Nunless the other spacer pairs are other than C(R_(XV-33))═C(R_(XV-35)),O, N, and S;

R_(XV-1) is selected from the group consisting of haloalkyl andhaloalkoxymethyl;

R_(XV-2) is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;

R_(XV-3) is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, and haloalkoxyalkyl;

Y_(XV) is selected from the group consisting of a covalent single bond,(CH₂)_(q) wherein q is an integer selected from 1 through 2 and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

Z_(XV) is selected from the group consisting of covalent single bond,(CH₂)_(q) wherein q is an integer selected from 1 through 2, and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

R_(XV-4), R_(XV-8), R_(XV-9) and R_(XV-13) are independently selectedfrom the group consisting of hydrido, halo, haloalkyl, and alkyl;

R_(XV-30) is selected from the group consisting of hydrido, alkoxy,alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl,alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso thatR_(XV-30) is selected to maintain the tetravalent nature of carbon,trivalent nature of nitrogen, the divalent nature of sulfur, and thedivalent nature of oxygen;

R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring linear spacer connecting the A_(XV-1)-carbon at the point ofattachment of R_(XV-30) to the point of bonding of a group selected fromthe group consisting of R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-31), andR_(XV-32) wherein said intra-ring linear spacer is selected from thegroup consisting of a covalent single bond and a spacer moiety havingfrom 1 through 6 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl having from 3 through 10 contiguous members,a cycloalkenyl having from 5 through 10 contiguous members, and aheterocyclyl having from through 10 contiguous members;

R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring branched spacer connecting the A_(XV-1)-carbon at the pointof attachment of R_(XV-30) to the points of bonding of each member ofany one of substituent pairs selected from the group consisting ofsubsitituent pairs R_(XV-10) and R_(XV-11), R_(XV-10) and R_(XV-31),R_(XV-10) and R_(XV-32), R_(XV-10) and R_(XV-12), R_(XV-11) andR_(XV-31), R_(XV-11) and R_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-31)and R_(XV-32), R_(XV-31) and R_(XV-12), and R_(XV-32) and R_(XV-12) andwherein said intra-ring branched spacer is selected to form two ringsselected from the group consisting of cycloalkyl having from 3 through10 contiguous members, cycloalkenyl having from 5 through 10 contiguousmembers, and heterocyclyl having from 5 through 10 contiguous members;

R_(XV-4), R_(XV-5), R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10),R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33),R_(XV-34), R_(XV-35) and R_(XV-36) are independently selected from thegroup consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy,cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy,aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl,perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the provisos that R_(XV-4), R_(XV-5),R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12),R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen, that no more than three ofthe R_(XV-33) and R_(XV-34) substituents are simultaneously selectedfrom other than the group consisting of hydrido and halo, and that nomore than three of the R_(XV-35) and R_(XV-36) substituents aresimultaneously selected from other than the group consisting of hydridoand halo;

R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), andR_(XV-32) are independently selected to be oxo with the provisos thatB_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are independently selected from the group consisting of C and S, no morethan two of R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13),R_(XV-31), and R_(XV-32) are simultaneously oxo, and that R_(XV-9),R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), and R_(XV-32) areeach independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

R_(XV-4) and R_(XV-5), R_(XV-5) and R_(XV-6), R_(XV-6) and R_(XV-7),R_(XV-7) and R_(XV-8), R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-11),R_(XV-11) and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) andR_(XV-12), and R_(XV-12) and R_(XV-13) are independently selected toform spacer pairs wherein a spacer pair is taken together to form alinear moiety having from 3 through 6 contiguous atoms connecting thepoints of bonding of said spacer pair members to form a ring selectedfrom the group consisting of a cycloalkenyl ring having 5 through 8contiguous members, a partially saturated heterocyclyl ring having 5through 8 contiguous members, a heteroaryl ring having 5 through 6contiguous members, and an aryl with the provisos that no more than oneof the group consisting of spacer pairs R_(XV-4) and R_(XV-5), R_(XV-5)and R_(XV-6), R_(XV-6) and R_(XV-7), R_(XV-7) and R_(XV-8) is used atthe same time and that no more than one of the group consisting ofspacer pairs R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-11), R_(XV-11)and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) and R_(XV-12), andR_(XV-12) and R_(XV-13) are used at the same time;

R_(XV-9) and R_(XV-11), R_(XV-9) and R_(XV-12), R_(XV-9) and R_(XV-13)R_(XV-9) and R_(XV-31), R_(XV-9) and R_(XV-32), R_(XV-10) and R_(XV-12),R_(XV-10) and R_(XV-13), R_(XV-10) and R_(XV-31), R_(XV) ₁₀ andR_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-11) and R_(XV-13), R_(XV-11)and R_(XV-32), R_(XV-12) and R_(XV-31), R_(XV-13) and R_(XV-31), andR_(XV-13) and R_(XV-32) are independently selected to form a spacer pairwherein said spacer pair is taken together to form a linear spacermoiety selected from the group consisting of a covalent single bond anda moiety having from 1 through 3 contiguous atoms to form a ringselected from the group consisting of a cycloalkyl having from 3 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, a saturated heterocyclyl having from 5 through 8 contiguousmembers and a partially saturated heterocyclyl having from 5 through 8contiguous members with the provisos that no more than one of said groupof spacer pairs is used at the same time;

R_(XV-37) and R_(XV-38) are independently selected from the groupconsisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo,haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl,haloalkoxy, and haloalkoxyalkyl.

Compounds of Formula XV and their methods of manufacture are disclosedin PCT Publication No. WO 00/18723, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XV:

3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifiuoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl[](3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl]](3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl](cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol:

3-[[3-(3-isopropylphenoxy)phenyl](cyclopentylmethyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-isopropylphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2.3-dichlorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(2,3-dichlorophenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl](cyclopropylmethyl)amino-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy]phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy]phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(3-trifluoromethylbenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl]phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-methylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-cyclohexyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl]phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifloromethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-isopropoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl)phenyl]methyl](3-cyclopentyloxycyclohexyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl]phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-pentafluoroethylcyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-propyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-difluropropyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]]3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;and

3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(phenoxy)propyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of (R)-chiral halogenated 1-substitutedamino-(n+1)-alkanols having the Formula XVI

and pharmaceutically acceptable forms thereof, wherein:

n_(XVI) is an integer selected from 1 through 4;

X_(XVI) is oxy;

R_(XVI-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R_(XVI-1) has a higher Cahn-Ingold-Prelog stereochemical systemranking than both R_(XVI-2) and (CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI)wherein A_(XVI) is Formula XVI-(II) and Q is Formula XVI-(III);

R_(XVI-16) is selected from the group consisting of hydrido, alkyl,acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from thegroup consisting of a covalent single bond and a linear spacer moietyhaving a chain length of 1 to 4 atoms linked to the point of bonding ofany aromatic substituent selected from the group consisting ofR_(XVI-4), R_(XVI-8), R_(XVI-9), and R_(XVI-13) to form a heterocyclylring having from 5 through 10 contiguous members;

D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one of D_(XVI-1),D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is a covalent bond, nomore than one D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1)is be O, no more than one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) is S, one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) must be a covalent bond when two of D_(XVI-1), D_(XVI-2),J_(XVI-1), J_(XVI-2) and K_(XVI-1) are O, and S, and no more than fourof D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is N;

D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one is a covalentbond, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) andK_(XVI-2) is O, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) S, no more than two of D_(XVI-3), D_(XVI-4),J_(XVI-3), J_(XVI-4) and K_(XVI-2) is O and S, one of D_(XVI-3),D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) must be a covalent bondwhen two of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areO and S, and no more than four of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) are N;

R_(XVI-2) is selected from the group consisting of hydrido, aryl,aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, andcarboalkoxycyanoalkyl, with the proviso that R_(XVI-2) has a lowerCahn-Ingold-Prelog system ranking than both R_(XVI-1) and(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI;)

R_(XVI-3) is selected from the group consisting of hydrido, hydroxy,cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl,heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl,carboxamide, and carboxamidoalkyl, with the provisos that(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI) has a lower Cahn-Ingold-Prelogstereochemical system ranking than R_(XVI-1) and a higherCahn-Ingold-Prelog stereochemical system ranking than R_(XVI-2);

Y_(XVI) is selected from a group consisting of a covalent single bond,(C(R_(XVI-14))₂)_(q) wherein q is an integer selected from 1 and 2 and(CH(R_(XVI-14)))_(—W) _(XVI—(CH(R) _(XVI-14)))_(p) wherein g and p areintegers independently selected from 0 and 1;

R_(XVI-14) is selected from the group consisting of hydrido, hydroxy,cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

Z_(XVI) is selected from a group consisting of a covalent single bond,(C(R_(XVI-15))₂)_(q), wherein q is an integer selected from 1 and 2, and(CH(R_(XVI-15)))_(j)—W_(XVI)—(CH(R_(XVI-5)))_(k) wherein j and k areintegers independently selected from 0 and 1;

W_(XVI) is selected from the group consisting of O, C(O),C(S),C(O)N(R_(XVI-14)), C(S)N(R_(XVI-14)),(R_(XVI-14))NC(O), (R_(XVI-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XVI-14)), (R_(XVI-14))NS(O)₂, andN(R_(XVI-14)) with the proviso that R_(XVI-14) is other than cyano;

R_(XVI-15) is selected, from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R_(XVI-4), R_(XVI-5), R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9),R_(XVI-10), R_(XVI-11), R_(XVI-12), and R_(XVI-13) are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl,heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl, amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoarylamidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that R_(XVI-4), R_(XVI-5),R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9), R_(XVI-10), R_(XVI-11),R_(XVI-12), and R_(XVI-13) are each independently selected to maintainthe tetravalent nature of carbon, trivalent nature of nitrogen, thedivalent nature of sulfur, and the divalent nature of oxygen;

R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), R_(XVI-7) and R_(XVI-8), R_(XVI-9) and R_(XVI-10), R_(XVI-10)and R_(XVI-11), R_(XVI-11) and R_(XVI-12), and R_(XVI-12) and R_(XVI-13)are independently selected to form spacer pairs wherein a spacer pair istaken together to form a linear moiety having from 3 through 6contiguous atoms connecting the points of bonding of said spacer pairmembers to form a ring selected from the group consisting of acycloalkenyl ring having 5 through 8 contiguous members, a partiallysaturated heterocyclyl ring having 5 through 8 contiguous members, aheteroaryl ring having 5 through 6 contiguous members, and an aryl withthe provisos that no more than one of the group consisting of spacerpairs R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), and R_(XVI-7) and R_(XVI-8) is used at the same time and thatno more than one of the group consisting of spacer pairs R_(XVI-9) andR_(XVI-10), R_(XVI-10) and R_(XVI-11), R_(XVI-11) and R_(XVI-12), andR_(XVI-12) and R_(XVI-13) can be used at the same time;

R_(XVI-4) and R_(XVI-9), R_(XVI-4) and R_(XVI-13), R_(XVI-8) andR_(XVI-9), and R_(XVI-8) and R_(XVI-13) is independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XVI-4) and R_(XVI-9), R_(XVI-4)and R_(XVI-13), R_(XVI-8) and R_(XVI-9), and R_(XVI-8) and R_(XVI-13) isused at the same time.

Compounds of Formula XVI and their methods of manufacture are disclosedin PCT Publication No. WO 00/18724, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XVI:

(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(1,1,2,2,-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(3-trifuoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-l1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(phenoxy)phenyl][[3(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-3-propanol;

(2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(N,N-dimethylamino,phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-3-propanol;

(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxyl-phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]l-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-flouro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]aminol-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(3R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and

(2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of quinolines of Formula XVII

and pharmaceutically acceptable forms thereof, wherein:

A_(XVII) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(XVII-4)R_(XVII-5) whereinR_(XVII-4) and R_(XVII-5) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

D_(XVII) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formula

wherein

R_(XVII-6), R_(XVII-7), R_(XVII-10) denote, independently from oneanother, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5- to 7-membered heterocyclecontaining up to 3 heteoatoms from the series of S, N and/or O, and/orin the form of a group according to the formula —OR_(XVII-11),—SR_(XVII-12), —SO₂R_(XVII-13), or —NR_(XVII-14)R_(XVII-15);

R_(XVII-11), R_(XVII-12), and R_(XVII-13) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

R_(XVII-14) and R_(XVII-15) are identical or different and have themeaning of R_(XVII-4) and R_(XVII-5) given above, or

R_(XVII-6) and/or R_(XVII-7) denote a radical according to the formula

R_(XVII-8) denotes a hydrogen or halogen, and

R_(XVII-9) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula NR_(XVII-16)R_(XVII-17),

R_(XVII-16) and R_(XVII-17) are identical or different and have themeaning of R_(XVII-4) and R_(XVII-5) above; or

R_(XVII-8) and R_(XVII-9) together form a radical according to theformula ═O or ═NR_(XVII-18);

R_(XVII-18) denotes a hydrogen or a straight-chain or branched alkyl,alkoxy or acyl containing up to 6 carbon atoms each;

L_(XVII) denotes a straight-chain or branched alkylene or alkenylenechain containing up to 8 carbon atoms each, which are optionallysubstituted with up to two hydroxyl groups;

T_(XVII) and X_(XVII) are identical or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms; or

T_(XVII) and X_(XVII) denotes a bond;

V_(XVII) denotes an oxygen or sulfur atom or —NR_(XVII-19);

R_(XVII-19) denotes a hydrogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms or a phenyl;

E_(XVII) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl;

R_(XVII-1) and R_(XVII-2) are identical or different and denote acycloalkyl containing 3 to 8 carbon atoms, hydrogen, nitro, halogen,trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, cyano, astraight-chain or branched acyl, alkoxycarbonyl or alkoxy with up to 6carbon atoms, or NR_(XVII-20)R_(XVII-21);

R_(XVII-20) and R_(XVII-21) are identical or different and denotehydrogen, phenyl, or a straight-chain or branched alkyl with up to 6carbon atoms; and or R_(XVII-1) and/or R_(XVII-2) are straight-chain orbranched alkyl with up to 6 carbon atoms, optionally substituted withhalogen, trifluoromethoxy, hydroxy, or a straight-chain or branchedalkoxy with up to 4 carbon atoms, aryl containing 6-10 carbon atomsoptionally substituted with up to five of the same or differentsubstituents selected from halogen, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, nitro, straight-chain or branched alkyl, acyl,hydroxyalkyl, alkoxy with up to 7 carbon atoms andNR_(XVII-22)R_(XVII-23);

R_(XVII-22) and R_(XVII-23) are identical or different and denotehydrogen, phenyl or a straight-chain or branched akyl up to 6 carbonatoms; and/or

R_(XVII-1) and R_(XVII-2) taken together form a straight-chain orbranched alkene or alkane with up to 6 carbon atoms optionallysubstituted with halogen, trifluoromethyl, hydroxy or straight-chain orbranched alkoxy with up to 5 carbon atoms;

R_(XVII-3) denotes hydrogen, a straight-chain or branched acyl with upto 20 carbon atoms, a benzoyl optionally substituted with halogen,trifluoromethyl, nitro or trifluoromethoxy, a straight-chained orbranched fluoroacyl with up to 8 carbon atoms and 7 fluoro atoms, acycloalkyl with 3 to 7 carbon atoms, a straight chained or branchedalkyl with up to 8 carbon atoms optionally substituted with hydroxyl, astraight-chained or branched alkoxy with up to 6 carbon atoms optionallysubstituted with phenyl which may in turn be substituted with halogen,nitro, trifluoromethyl, trifluoromethoxy, or phenyl or a tetrazolsubstitued phenyl, and/or an alkyl that is optionally substituted with agroup according to the formula —OR_(XVII-24);

R_(XVII-24) is a straight-chained or branched acyl with up to 4 carbonatoms or benzyl.

Compounds of Formula XVII and their methods of manufacture are disclosedin PCT Publication No. WO 98/39299, which is incorporated herein byreference in its entirety for all purposes.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 4-Phenyltetrahydroquinolines of Formula XVIII,

N oxides thereof, and pharmaceutically acceptable forms thereof,wherein:

A_(XVIII) denotes a phenyl optionally substituted with up to twoidentical or different substituents in the form of halogen,trifluoromethyl or a straight-chain or branched alkyl or alkoxycontaining up to three carbon atoms;

D_(XVIII) denotes the formula

R_(XVIII-5) and R_(XVIII-6) are taken together to form ═O; or

R_(XVIII-5) denotes hydrogen and R_(XVIII-6) denotes halogen orhydrogen; or

R_(XVIII-5) and R_(XVIII-6) denote hydrogen;

R_(XVIII-7) and R_(XVIII-8) are identical or different and denotephenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl withup to four identical or different substituents in the form of halogen,trifluoromethyl, nitro, cyano, trifluoromethoxy, —SO₂—CH₃ orNR_(XVIII-9)R_(XVIII-10);

R_(XVIII-9) and R_(XVIII-10) are identical or different and denotehydrogen or a straight-chained or branched alkyl of up to three carbonatoms;

E_(XVIII) denotes a cycloalkyl of from three to six carbon atoms or astraight-chained or branched alkyl of up to eight carbon atoms;

R_(XVIII-1) denotes hydroxy;

R_(XVIII-2) denotes hydrogen or methyl;

R_(XVIII-3) and R_(XVIII-4) are identical or different and denotestraight-chained or branched alkyl of up to three carbon atoms; or

R_(XVIII-3) and R_(XVIII-4) taken together form an alkenylene made up ofbetween two and four carbon atoms.

Compounds of Formula XVIII and their methods of manufacture aredisclosed in PCT Publication No. WO 99/15504 and U.S. Pat. No.6,291,477, both of which are incorporated herein by reference in theirentireties for all purposes.

The present invention is particularly advantageous for the class ofdrugs which are both acid-sensitive and low-solubility. Exemplaryacid-sensitive, low-solubility drugs include(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;

lansoprazole; and progabide; as well as CCR1 inhibitors such asquinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amideand quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide.

The invention is useful for improving the intrinsic dissolution rate ofcompounds selected from the following. The intrinsic dissolution rate isdefined as the rate of dissolution of a pure pharmaceutical activeingredient when conditions such as surface area, agitation-stirringspeed, pH and ionic-strength of the dissolution medium are keptconstant. Intrinsic dissolution rate is further defined as beingmeasured in water at 37° C. using a USP II dissolution apparatusequipped with a Wood's apparatus (Wood, J H; Syarto, J E and Letterman,H: J.Pharm. Sci. 54 (1965), 1068) with a stirring speed of 50 rpm. Theintrinsic dissolution rate is defined in terms of mg of drug dissolvedper minute from a unit surface area, therefore, the intrinsicdissolution rate is referred to in units of mg/min.cm².

The compositions and methods of the invention are particularly usefulfor compounds with an intrinsic dissolution rate of preferably less than0.1 mg/min.cm²and more preferably with less than 0.05 mg/min.cm².

Turning now to the chemical structures of specific CCR1 inhibitors, oneclass of CCR1 inhibitors that finds utility with the present inventionconsists of dihydroxyhexanoic acid derivatives having the Formula CCR1-I

wherein R_(I) is (C₂-C₉) heteroaryl optionally substituted with one, twoor three substituents independently selected from the group consistingof hydrogen, halo, cyano, (C₁-C₆)alkyl optionally substituted with one,two or three fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein R₂ is phenyl-(CH₂)_(m)—, naphthyl-(CH₂)_(m)—,(C₃-C₁₀)cycloalkyl-(CH₂)_(m)—, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl-(CH₂)_(m)—, wherein each of said phenyl, naphthyl,(C₃-C₁₀)cycloalkyl or (C₂-C₉)heteroaryl moieties of saidphenyl-(CH₂)_(m)—, naphthyl-(CH₂)_(m)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(m)— or(C₂-C₉)heteroaryl-(CH₂)_(m)— groups may optionally be substituted withone, two, or three substituents independently selected from the groupconsisting of hydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C,-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,phenoxy, benzyloxy, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and(C₂-C₉)heteroaryl;

wherein R³ is hydrogen, (C₁-C₁₀)alkyl, (C₃-C₁₀)cycloalkyl-(CH₂)_(n)—,(C₂-C₉)heterocycloalkyl-(CH₂)_(n)—, (C₂-C₉)heteroaryl-(CH₂)_(n)— oraryl-(CH₂)_(n)—; wherein n is an interger from zero to six;

wherein said R₃ (C₁-C₁₀)alkyl group may optionally be substituted withone or more substituents, (preferably from one to three substituents)independently selected from hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂-NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; andwherein any of the carbon-carbon single bonds of said (C₁-C₁₀)alkyl mayoptionally be replaced by a carbon-carbon double bond;

wherein the (C₃-C₁₀)cycloalkyl moiety of said R₃(C₃-C₁₀)cycloalkyl-(CH₂)_(n)— group may optionally be substituted by oneto three substitutents independently selected from the group consistingof hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkyl HN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein the (C₂-C₉)heterocycloalkyl moiety of said R₃(C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur,oxygen, >S(═O), >SO₂ or >NR⁶, wherein said (C₂-C₉)heterocycloalkylmoiety of said (C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may optionallybe substituted on any of the ring carbon atoms capable of forming anadditional bond (preferably one to three substitutents per ring) with asubstituent independently selected from the group consisting ofhydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein the (C₂-C₉)heteroaryl moiety of said R³(C₂-C₉)heteroaryl-(CH₂)_(n)— group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur or oxygen,wherein said (C₂-C₉)heteroaryl moiety of said(C₂-C₉)heteroaryl-(CH₂)_(n)— group may optionally be substituted on anyof the ring carbon atoms capable of forming an additional bond(preferably one to three substitutents per ring) with a substituentselected from the group consisting of hydrogen, halo, CN, (C₁-C₆)alkyl,hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; and

wherein said aryl moiety of said R₃ aryl-(CH₂)_(n)— group is optionallysubstituted phenyl or naphthyl, wherein said phenyl and naphthyl mayoptionally be substituted with from one to three substituentsindependently selected from the group consisting of hydrogen, halo, CN,(C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkyl HN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

or R₃ and the carbon to which it is attached form a five to sevenmembered carbocyclic ring, wherein any of the carbon atoms of said fivemembered carbocyclic ring may optionally be substituted with asubstituent selected from the group consisting of hydrogen, halo, CN,(C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;wherein one of the carbon-carbon bonds of said five to seven memberedcarbocyclic ring may optionally be fused to an optionally substitutedphenyl ring, wherein said substitutents may be independently selectedfrom hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein R₄ is hydrogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C═O)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(q)—,(C₂-C₉)heterocycloalkyl-(CH₂)_(q)—, (C₂-C₉)heteroaryl-(CH₂)_(q)—,phenyl-(CH₂)_(q)—, or naphthyl-(CH₂)_(q)—; wherein said(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl, phenyl and naphthyl groupsmay be optionally substituted with one or two substituents from thegroup consisting of hydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂ amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino (C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein R₅ is hydrogen, (C₁-C₆)alkyl or amino; or

R₄ and R₅ together with the nitrogen atom to which they are attachedform a (C₂-C₉)heterocycloalkyl group optionally substituted with one ortwo substituents selected from the group consisting of hydrogen, halo,cyano, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆) alkyl(O═C)—,(C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂ amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—, H₂N(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl,H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH, (C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₈)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein R⁶ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy-(CH₂)_(g)—.(C₁-C₆)alkoxy(C═O)—(CH₂)_(g)—, (C₁-C₆)alkyl-(SO₂)—(CH₂)_(g)—,(C₆-C₁₀)aryloxy-(CH₂)_(g)—, (C₆-C₁₀)aryloxy(C═O)—(CH₂)_(g)—, or(C₆-C₁₀)aryl-(SO₂)—(CH₂)_(g)—;

wherein g is an integer from zero to four;

wherein m is an integer from zero to four;

wherein n is an interger from zero to six;

with the proviso that when one of R⁴ or R⁵ is hydrogen, and the other ofR⁴ or R⁵ is (C₁-C₆)alkyl; R² is (C₃-C₁₀)cycloalkyl or isopropyl and R³is (C₃-C₅)alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl,hydroxy(C₁-C₃)alkyl or amino(C₁-C₄)alkyl then R¹ must be other thanindol-5-yl, 6-azaindol-2-yl, 2,3-dichloro-pyrrol-5-yl,4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl, oroptionally substituted indol-2 or 3-yl;

and the pharmaceutically acceptable salts of such compounds.

Unless otherwise indicated, the alkyl and alkenyl groups referred toherein, as well as the alkyl moieties of other groups referred to herein(e.g., alkoxy), may be linear or branched, and they may also be cyclic(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl)or be linear or branched and contain cyclic moieties. Such alkyl andalkoxy groups may be substituted with one, two or three halogen and/orhydroxy atoms, preferably fluorine atoms.

Unless otherwise indicated, “halogen” includes fluorine, chlorine,bromine, and iodine.

“(C₃-C₁₀)cycloalkyl” when used herein refers to cycloalkyl groupscontaining zero to two levels of unsaturation such as cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane,norbornanyl, and the like.

“(C₂-C₉)heterocycloalkyl” when used herein refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, and the like. One ofordinary skill in the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon or a sp³ hybridizednitrogen heteroatom.

“(C₂-C₉)heteroaryl” when used herein refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl, and the like. One of ordinaryskill in the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon atom or a sp³hybridized nitrogen heteroatom.

“Aryl” when used herein refers to phenyl or naphthyl.

“Protected amine” and “protected amino” refers to an amine group withone of the hydrogen atoms replaced with a protecting group (P). Anysuitable protecting group may be used for amine protection. Suitableprotecting groups include carbobenzyloxy, t-butoxy carbonyl (BOC) or9-fluorenyl-methylenoxy carbonyl.

Compounds of Formula CCR1-I and their methods of manufacture aredisclosed in commonly assigned U.S. patent application Ser. No.09/380,269, filed Feb. 5, 1998, U.S. patent application Ser. No.09/403,218, filed Jan. 18, 1999, PCT Publication No. WO98/38167, and PCTPublication No. WO99/40061, all of which are incorporated herein byreference in their entireties for all purposes.

In a preferred embodiment, the CCR1 inhibitor is selected from one ofthe following compounds of Formula CCR1-I:

quinoxaline-2-carboxylic acid4(R)-carbamoyl-1(S)-(3-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

7,8-difluoro-quinoline-3-carboxylic acid(1S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;

6,7,8-trifluoro-quinoline-3-carboxylic acid(1(S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;

quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

quinoxaline-2-carboxylic acid(1(S)-benzyl-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl)-amide;

quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(2-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

quinoxaline-2-carboxylic acid[1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;

quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

quinoxaline-2-carboxylic acid[1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;

quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

quinoxaline-2-carboxylic acid(4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-1(S)-naphthalen-1-ylmethyl-octyl)-amide;

7,8-difluoro-quinoline-3-carboxylic acid1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;

8-fluoro-quinoline-3-carboxylic acid1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;

quinoxaline-2-carboxylic acid[4(R)-carbamoyl-7-fluoro-1-(3(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;

quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1-(2(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;

quinoxaline-2-carboxylic acid[1(S)-benzyl-4(S)-carbamoyl-4(S)-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2(S)-hydroxy-butyl]-amide;

quinoxaline-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide;

quinoxaline-2-carboxylic acid1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide;

quinoxaline-2-carboxylic acid1(S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;

quinoxaline-2-carboxylic acid[1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;

quinoxaline-2-carboxylic acid[1(S)-benzyl-4(S)-(4,4-difluoro-1-hydroxy-cyclohexyl)-2(S)-hydroxy-4-hydroxycarbamoyl-butyl]-amide;

quinoxaline-2-carboxylic acid[1(S)-benzyl-4(S)-carbamoyl-4(S)-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-butyl]-amide;

quinoline-3-carboxylic acid(1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide;

quinoxaline-2-carboxylic acid(4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiophen-2-ylmethyl-octyl)-amide;

quinoxaline-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-oct-6-enyl)-amide;

quinoxaline-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide;

N-1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-5,6-dichloro-nicotinamide;

quinoxaline-2-carboxylic acid(4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiazol-4(R)-ylmethyl-octyl)-amide;

benzothiazole-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide;and

benzofuran-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide.

In another preferred embodiment, the CCR1 compound has a formula la-1:

wherein the substituents are as defined above.

In a preferred method of making the compound Ia-1, the reaction isstarted with Scheme 1. In the herein described processes, thesubstituents are as defined for CCR1-I, and the following:

R₇ is hydroxy, (C₁-C₆)alkyl, or phenyl wherein the phenyl groupunsubstituted or substituted with one, two, or three (C₁-C₆)alkyl,hydroxy, or halogen groups;

R₈ is hydroxy or halogen;

R₉ is phenyl, naphthyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl, wherein each of said phenyl, naphthyl,(C₃-C₁₀)cycloalkyl or (C₂-C₉)heteroaryl groups may be unsubstituted orsubstituted with one, two, or three substituents independently selectedfrom the group consisting of halogen, cyano, and (C₁-C₆)alkyl;

P is a protecting group;

X is hydroxy or halogen; and

q is 0, 1, 2, 3, or 4.

In scheme 1 step 1, a compound of the formula (VI-1) is reduced with areducing agent under heat to form a compound of the formula (VId-1). Inone embodiment, the reducing agent is aluminum triisopropoxide andisopropanol. Preferably, the temperature is maintained above roomtemperature, more preferably between about 60° C. and about 82° C. Theproduct alcohol can be isolated by either cooling the reaction mixtureto room temperature, diluting with more isopropanol and collecting thecrystalline material or by cooling the reaction to room temperature andadding 1N HCL and water and collecting the crystalline material.

Step 2 of scheme 1 includes reacting a compound of the formula R₇—SO₂—Xand a compound of the formula (VId-1) in the presence of a base to formthe compound of the formula (VIe-1). Any amine base is suitable,including pyridine, triethylamine, N-methylmayholine, anddiisoyropylethylamine. In one embodiment, R₇—SO₂—R₈ is p-toluenesulfonicacid, methanesulfonic acid, sulfuric acid, or methanesulfonyl chloride.In another embodiment, the conversion of hydroxy dioxane (VId-1) todioxane oxazolidinone (VIe-1) can be achieved by treatment of thehydroxy dioxane (VId-1) with methanesulfonyl chloride and triethylaminein tetrahydrofuran solution and heating the mixture to cause thecyclization of the mesylate formed in situ to the oxazolidinone.

In step 3 of scheme 1, a compound of the formula (VIf-1) may be formedby heating the compound of the formula (VIe-1). The reaction may proceedby dissolving compound VIe-1 in a solvent such as pyridine or N-methylimidazole and heating the mixture for several hours at temperature fromabout 50° C. to about 100° C.; preferably at about 80° C. The mesylate(VIf-1) may be recovered by extraction into an organic solvent such asethyl acetate and removal of the amine solvents by extraction of thesolution with aqueous acid.

Step 4 of scheme 1 depicts reacting hydroxylamine hydrochloride, acompound of the formula R₇—SO₂—X, and a compound of the formula (VIf-1)to form a compound of the formula (VIg-1). In one embodiment, R₇—SO₂-Xis p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, ormethanesulfonyl chloride. The reaction may occur in a solvent, such asmethanol. In one embodiment, the reaction occurs in methanol with tosicacid at reflux for 8 to 24 hours. The resulting nitrile oxazolidinonecontains a small amount of the corresponding ethyl ester which is notremoved since it also is converted to the desired lactone in subsequentsteps.

Step 5 of scheme 1 includes a) hydrolyzing a compound of the formula(VIg-1) with an aqueous solution in the presence of a base, b)protecting the amine group of the compound so formed, and c) cyclizingthe compound so formed with heat and an acid catalyst. In oneembodiment, the compound VIg-1 is hydrolyzed with sodium hydroxide. ThepH is adjusted to approximately 10 and tetrahydrofuran and BOCdicarbonate are added. This provides the protected hydroxy acid, whichmay be heated in 10% acetic acid and toluene to provide the protectedamine lactone (V-1).

The compound of formula (V-1) may also be produced according to scheme2.

In step 1 of scheme 2, a compound of the formula (VI-1) may be reactedwith ozone to for a compound of the formula (VIa-1). The compound VI-1may be present in a solvent, such as ethyl acetate, and the ozoneintroduced through sparging at a temperature below room temperature,preferably at about −15° C., until the starting dioxane ketone issubstantially reacted. Any excess ozone may be removed by bubblingnitrogen through the solution. The resulting crude ketone ester mixturemay be isolated after treatment with aqueous sodium bisulfite to removeany hydroperoxides.

Alternatively, in step 1 of scheme 2, the compound of the formula(VIa-1) may be formed by reacting hypochlorous acid and a compound ofthe formula (VI-1). Such an oxidation reaction typically produceschlorinated forms of the compound VIa-1 as side products in addition othe compound VIa-1. This oxidation reaction proceeds by mixing thecompound VI-1 in solvent, such as acetic acid and/or acetone, and addingsodium hypochlorite, while keeping the mixture at a low temperature,preferably at or below about 0° C.

As a means to convert the side product chlorinated forms of the compoundVIa-1 to compounds of the formula V-1, the compounds formed from thehypochlorous acid oxidation reaction may optionally be hydrogenated byreaction with hydrogen in the presence of a catalyst. The hydrogenationmay include introducing the products from the hypochlorous acidoxidation reaction into a solvent system of tetrahydrofuran and water,followed by addition of a Pd/C catalyst. The resulting mixture issubjected to hydrogen above atmospheric pressure and temperature. In oneembodiment, the pressure is about 80 pounds per square inch and thetemperature is maintained from about 60° C. to about 70° C. until thereaction is substantially complete.

In step 2 of scheme 2, the compound of the formula (VIb-1) may be formedby reacting a silyating,agent and a compound of the formula (VIa-1) andreacting the compound so formed with a reducing agent. In oneembodiment, the reducing agent is N-selectride. In another emodiment,the silyating agent is 1,1,1,3,3,3-hexamethyl-disilazane. The reductionreaction may occur at temperatures below about 0° C., preferably belowabout −20° C., more preferably below about −50° C. In addition, thereducing agent may be present in slight excess.

In step 3 of scheme 2, the compound of the formula (V-1) is formed byheating a compound of the formula (VIb-1) in the presence of an acidcatalyst, such as acetic acid. In one embodiment, the cyclizationreaction occurs by introducing the compound VIb-1 into a solventmixture, such as toluene and 10% acetic acid, at the solvent refluxtemperature for 8 to 16 hours. This provides the desired lactone as acrystalline solid after work up.

One method of making the compound of the formula (VI-1) is by reacting acompound of the formula (VII-1)

with a Grinard reagent formed in situ by addition of2-(2-bromo-ethyl)-[1,3]dioxane to a mixture comprising magnesium and thecompound of the formula (VII-1). In one embodiment, the mixture furthercomprises methyl magnesium chloride and/or methyl magnesium bromide in asolvent. Any exotherm formed from the reaction may be controlled by therate of addition of the bromide.

The compound of the formula (VII-1) may be formed by couplingN,O-dimethylhydroxylamine hydrochloride and a compound of the formula(VIII-1)

This coupling reaction may be performed by mixed anhydride procedure. Inone mixed anhydride procedure, compound VIII-1 is combined withmethylene chloride and N-methylmorpholine is added followed by isobutylchloroformate. In a separate mixture, a slurry ofN,O-dimethylhydroxylamine hydrochloride is treated withN-methylmorpholine. The two reaction mixtures are combined and thenquenched with a solution of citric acid in water. This procedurepreferably operates at a temperature below about 20° C., more preferablybelow about 0° C.

Compounds of formula (V-1) may be used to produce compounds of theformula (IVa1-1) according to scheme 3:

In step 1 of scheme 3, the compound of the formula (IVal-1) may beformed by reacting 4-halo-2-methyl-2-butene and a compound of theformula (V-1) in the presence of a base. Exemplary bases include lithiumdialkyl amides such as lithium N-isopropyl-N-cyclohexylamide, lithiumbis(trimethylsilyl)amide, lithium di-isopropylamide, and potassiumhydride. Suitable solvents include aprotic polar solvents such as ethers(such as tetrahydrofuran, glyme or dioxane), benzene, or toluene,preferably tetrahydrofuran. The aforesaid reaction is conducted at atemperature from about −78° C. to about 0° C., preferably at about −78°C. In one embodiment, alkylation of the lactone (V-1) is accomplished byreacting the lactone (V-1) with lithium bis(trimethylsilyl)amide anddimethylallyl bromide in tetrahydrofuran at a temperature from about−78° C. to about −50° C. Reaction times range from several hours or ifan additive such as dimethyl imidazolidinone is present, the reactionmay be complete in minutes.

Compounds of formula (IVa1-1) may be used to produce compounds of theformula (Ia-1) according to scheme 4:

In step 1 of scheme 4, a compound of the formula (IIIa1-1) is formed byreacting a compound of the formula.(IVa1-1) with phosphoric acid.Preferably, this reaction occurs in any suitable solvent, such asnon-alcoholic solvents. Two preferred solvents include tetrahydrofuranand dichloroethane. The reaction may take place at any suitabletemperature, preferably from about −25° C. to about 120° C., morepreferably from about 15° C. to about 40° C. Reaction time is dependenton temperature and batch size, amount other factors, but typicallyreaction time is from about 2 hours to about 14 hours.

Step 2 of scheme 4 depicts coupling a compound IIIa1-1 with a compoundhaving the formula R₁—CO—X to form a compound having the formula(IIa1-1). This coupling reaction is generally conducted at a temperaturefrom about −30° C. to about 80° C., preferably from about 0° C. to about25° C. The coupling reaction may occur with a coupling reagent thatactivates the acid functionality. Exemplary coupling reagents includedicyclohexylcarbodiimide/hydroxybenzotriazole (DCC/HBT),N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC/HBT),2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI), and diethylphosphorylcyanide. The coupling isconducted in an inert solvent, preferably an aprotic solvent, such astetrahydrofuran, acetonitirile, dichloromethane, chloroform, orN,N-dimethylformamide. One preferred solvent is tetrahydrofuran. In oneembodiment, quinoxaline acid is combined with CDI in anhydroustetrahydrofuran and heated to provide the acyl imidazole. CompoundIIIa1-1 is added to the acyl imidazole at room temperature to form thecompound IIa1-1.

Step 3 of scheme 4 includes reacting the compound of formula IIa1-1withan amine having a formula NHR₄R₅ to form a compound of the formula(Ia-1). In one embodiment, the amine is ammonia either anhydrous in anorganic solvent or as an aqueous solution of ammonium hydroxide added toa polar solvent at a temperature from about −10° C. to about 35° C.,preferably at about 30° C. Suitable solvents include, alcohols, such asmethanol, ethanol, or butanols; ethers such as tetrahydrofuran, glyme ordioxane; or a mixture thereof, including aqueous mixtures. Preferablythe solvent is methanol. In one embodiment, the compound IIa1-1 isdissolved in methanol which has been saturated with ammonia gas. Inanother embodiment, the compound IIa1-1 in methanol is treated withammonium hydroxide in tetrahydrofuran at room temperature.

Scheme 5 represents an alternative method to form compounds of formulaIa-1 from compounds of formula IVa1-1.

In step 1 of scheme 5, a compound of the formula (IVa1-1) is reactedwith a compound of the formula R₉—SO₂—X to form a compound of theformula (IVa2-1). Any suitable acidic deprotection reaction may beperformed. In one example, an excess of p-toluenesulfonic acid hydratein ethyl acetate is introduced to the compound IVa1-1 at roomtemperature. Suitable solvents include ethyl acetate, alcohols,tetrahydrofuran, and mixtures thereof. The reaction may proceed atambient or elevated temperatures. Typically, the reaction issubstantially complete within two and twelve hours. The resultingcompound IVa2-1 may be crystallized and separated from the reactionmixture, and may be further purified to remove impurities byrecrystallization from hot ethyl acetate.

In step 2 of scheme 5, the compound IVa2-1 may be coupled with acompound having the formula R₁—CO—X to form a compound of the formula(IIIa2-1). This coupling reaction is generally conducted at atemperature from about−30° C. to about 80° C., preferably from about 0°C. to about 25° C. The coupling reaction may occur with a couplingreagent that activates the acid functionality.

Exemplary coupling reagents includedicyclohexylcarbodiimide/hydroxybenzotriazole (DCC/HBT),N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC/HBT),2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI)/dimethylaminopyridine (DMAP), anddiethylphosphorylcyanide. The coupling is conducted in an inert solvent,preferably an aprotic solvent, such as acetonitirile, dichloromethane,chloroform, or N,N-dimethylformamide. One preferred solvent is methylenechloride. In one embodiment, quinoxaline acid is combined with methylenechloride, oxalyl chloride and a catalytic amount ofN,N-dimethylformamide to form an acid chloride complex. The compoundIVa2-1 is added to the acid chloride complex followed by triethylamineat a temperature from about 0° C. to about 25° C. to form the compoundIIIa2-1.

Step 3 of scheme 5 includes reacting a compound IIIa2-1 withtrifluoroacetic acid to produce a compound of the formula (IIIa2-1). Inone embodiment, the hydration with trifluoroacetic acid occurs inmethylene chloride solution at room temperature. The hydration may takeseveral hours to complete at room temperature. A catalytic amount ofsulfuric acid can be added to the reaction solution to increase the rateof reaction.

Step 4 of scheme 5 includes reacting the compound of formula IIa2-1 withan amine having a formula NHR₄R₅ to form a compound of the formula(Ia-1). In one embodiment, the amine is ammonia either anhydrous in anorganic solvent or as an aqueous solution of ammonium hydroxide added toa polar solvent at a temperature from about −10° C. to about 35° C.,preferably at about 30° C. Suitable solvents include, alcohols, such asmethanol, ethanol, or butanols; ethers such as tetrahydrofuran, glyme ordioxane; or a mixture thereof, including aqueous mixtures. Preferablythe solvent is methanol. In one embodiment, the compound IIa2-1 isdissolved in methanol which has been saturated with ammonia gas. Inanother embodiment, the compound IIa2-1 in methanol is treated withammonium hydroxide in tetrahydrofuran at room temperature.

Adsorbates

The drug is present in the composition in the form of an adsorbatecomprising a drug and a substrate. At least a major portion of the drugin the adsorbate is amorphous. The term “amorphous” indicates simplythat the drug is not crystalline as indicated by any conventionalmethod, such as by powder X-ray diffraction (PXRD) analysis in which thesharp scattering lines associated with the crystal forms of the drug areabsent or reduced in magnitude or the absence of an endothermictransition at the melting point of the crystalline drug when subjectedto thermal analysis. The term “a major portion” of the drug means thatat least 60% of the drug is in amorphous form, rather than a crystallineform. Preferably, the drug in the adsorbate is substantially amorphous.As used herein, “substantially amorphous” means that the amount of thedrug in amorphous form is at least 80%. More preferably, the drug in theadsorbate is “almost completely amorphous” meaning that the amount ofdrug in the amorphous form is at least 90% as measured by powder X-raydiffraction or differential scanning calorimetry (“DSC”), or any otherstandard quantitative measurement. Most preferrably, the drug in theadsorbate is in a completely amorphous form within the detection limitsof the techniques used for characterization.

The adsorbate also includes a high surface area substrate. The substratemay be any material that is inert, meaning that the substrate does notadversely interact with the drug to an unacceptably high degree andwhich is pharmaceutically acceptable. The substrate also has a highsurface area, meaning that the substrate has a surface area of at least20 m²/g, preferably at least 50 m²/g, more preferably at least 100 m²/g,and most preferably at least 180 m²/g. The surface area of the substratemay be measured using standard procedures. One exemplary method is bylow-temperature nitrogen adsorption, based on the Brunauer, Emmett, andTeller (BET) method, well known in the art. As discussed below, thehigher the surface area of the substrate, the higher thedrug-to-substrate ratio that can be achieved and still maintain highconcentration-enhancements and improved physical stability. Thus,effective substrates can have surface areas of up to 200 m²/g, up to 400m²/g and up to 600 m²/g or more. The substrate should also be in theform of small particles ranging in size of from 10 nm to 1 μm,preferably ranging in size from 20 nm to 100 nm. These particles may inturn form agglomerates ranging in size from 10 nm to 100 μm. Thesubstrate is also insoluble in the process environment used to form theadsorbate. That is, where the adsorbate is formed by solvent processing,the substrate does not dissolve in the solvent. Where the adsorbate isformed by a melt or thermal process, the adsorbate has a sufficientlyhigh melting point that it does not melt.

Exemplary materials which are suitable for the substrate includeinorganic oxides, such as SiO₂, TiO₂, ZnO₂, ZnO, Al₂O₃, MgAlSilicate,CaSilicate, AlOH₂, zeolites, and other inorganic molecular seives; waterinsoluble polymers, such as cross-linked cellulose acetate phthalate,cross-linked hydroxypropyl methyl cellulose acetate succinate,cross-linked polyvinyl pyrrolidinone, (also known as cross povidone)microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer,polyethylene polyvinyl pyrrolidone copolymer, cross-linked carboxymethylcellulose, sodium starch glycolate, cross-linked polystyrene divinylbenzene; and activated carbons, including those made by carbonization ofpolymers such as polyimides, polyacylonitrile, phenolic resins,cellulose acetate, regenerated cellulose, and rayon.

The surface of the substrate may be modified with various substituentsto achieve particular interactions of the drug with the substrate. Forexample, the substrate may have a hydrophobic or hydrophilic surface. Byvarying the terminating groups of substituents attached to thesubstrate, the interaction between the drug and substrate may beinfluenced. For example, where the drug is hydrophobic, it may bedesired to select a substrate having hydrophobic substituents to improvethe binding of the drug to the substrate.

Generally, the interaction of drug with the substrate should besufficiently high such that mobility of the drug in the drug/substrateadsorbate is sufficiently decreased such that the composition hasimproved stability, as described below. However, the drug/substrateinteraction should be sufficiently low such that the drug can readilydesorb from the adsorbate when it is introduced to a use environment,resulting in a high concentration of drug in solution.

The adsorbates are formed so as to form a thin layer of amorphous drugon the surface of the substrate. By “thin layer” is meant a layer thatranges in average thickness from less than one drug molecule to as manyas 10 molecules. When the drug/substrate interaction is large and theaverage drug layer thickness, based on ratio of the mass ofdrug-to-substrate surface area, is about the dimensions of one molecule,the drug layer is generally termed a “monolayer.”

The adsorption of drug to the substrate may be characterized by a shiftin the infra red (IR) spectra of the drug, indicating interaction of thedrug with the substrate. Such interactions are generally due to Londondispersion forces, dipole-dipole interactions, hydrogen bonding,electron donor-electron acceptor interactions or ionic interactions.Thus, as the number of layers of molecules on the substrate increases,the average shift of the IR absorption decreases. That is, the IRspectrum will show a composite of those molecules that are in contactwith the substrate surface as well as those that are further away fromthe surface. Additionally, if the adsorbate contains more than 2 or 3layers of drug molecules, the physical stability of the adsorbate may becompromised, since the mobility of the drug molecules furthest from thesubstrate is relatively high. Thus, crystallization of the drugmolecules on a thick adsorbed layer may occur more rapidly than thatobserved for a thin adsorbed layer.

One exemplary method for forming adsorbates of the present invention is“solvent processing.” Solvent processing consists of dissolution of thedrug in a solvent containing the substrate followed by rapid removal ofthe solvent. The term “solvent” is used broadly and includes mixtures ofsolvents. In general, the substrate will not significantly dissolve inthe solvent and remains solid throughout the process.

First, the substrate is added to a solvent which is capable ofdissolving the drug. Since it is generally desirable to form adsorbateparticles that are small, preferably less than about 1 to 10 μm, thesolution is agitated to form a suspension of small particles ofsubstrate suspended in the solvent. Agitation of the solution may beperformed by any method that is capable of imparting sufficient energyto the solution to break up agglomerations of substrate particles. Apreferred method is sonication. Other methods which may be used to breakup the particles to form a suspension of substrate in the solventinclude high speed mixing, and high shear mechanical mixing. Thesolution is agitated for a sufficient length of time so that thesubstrate remains suspended in the solution for at least a few minutes.Often, to ease processing, it is desirable that the substrate remainsuspended for at least 60 minutes without agglomeration. However, thisis not required for practice of the invention. The solvent/substratesuspension may be continuously agitated during processing to ensure thesubstrate remains suspended in the solvent.

The drug is then added to the solvent and dissolved. The amount of drugand substrate present in the solution is chosen to yield an adsorbatehaving the desired ratio of drug to substrate. In general, good resultsmay be obtained where the solution comprises from 0.1 to 2 wt % drug andfrom 0.1 to 5 wt % substrate. In general, it is desired to maintain theamount of solids in the solution at less than about 10 wt %, as thesubstrate when present at higher concentrations may clog or stick to thesurfaces of the apparatus used to form the adsorbate. The weight ratioof drug to substrate is chosen such that the desired drug-layerthickness is obtained. Generally, better dissolution performance isobtained at lower drug-to-substrate ratios. However, higherdrug-to-substrate weight ratios provide good performance when thesubstrate surface area is high. Typically, drug-to-substrate weightratios are less than 1.0 and often less than 0.25 to obtain preferreddissolution performance.

After the substrate has been agitated and the drug has been dissolved,the solvent is rapidly removed by evaporation or by mixing with anon-solvent. Exemplary processes are spray-drying, spray-coating(pan-coating, fluidized bed coating, etc.), and precipitation by rapidmixing of the solution with CO₂, hexane, heptane, water of appropriatepH, or some other non-solvent. Preferably, removal of the solventresults in a solid adsorbate. To achieve this end, it is generallydesirable to rapidly remove the solvent from the solution such as in aprocess where the solution is atomized and the drug rapidly solidifieson the substrate.

The adsorbates formed by such processes that rapidly “quench” thematerial, that is, bring the material from the dissolved state to thesolid state very rapidly are generally preferred as they result in amaterial with superior physical structure and performance.

In one embodiment, the solvent is removed through the process ofspray-drying. The term spray-drying is used conventionally and broadlyrefers to processes involving breaking up liquid mixtures into smalldroplets (atomization) and rapidly removing solvent from the mixture ina container (spray-drying apparatus) where there is a strong drivingforce for evaporation of solvent from the droplets. The strong drivingforce for solvent evaporation is generally provided by maintaining thepartial pressure of solvent in the spray-drying apparatus well below thevapor pressure of the solvent at the temperature of the drying droplets.This is accomplished by either (1) maintaining the pressure in thespray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2)mixing the liquid droplets with a warm drying gas; or (3) both. Inaddition, at least a portion of the heat required for evaporation ofsolvent may be provided by heating the spray solution.

Solvents suitable for spray-drying can be water or any organic compoundin which the drug is soluble and the substrate insoluble. Preferably,the solvent is also volatile with a boiling point of about 150□C. orless. In addition, the solvent should have relatively low toxicity andbe removed from the adsorbate to a level that is acceptable according toThe International Committee on Harmonization (ICH) guidelines. Removalof solvent to this level may require a processing step such astray-drying subsequent to the spray-drying or spray-coating process.Preferred solvents include alcohols such as methanol, ethanol,n-propanol, isopropanol, and butanol; ketones such as acetone, methylethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetateand propylacetate; and various other solvents such as acetonitrile,methylene chloride, toluene, and 1,1,1-trichloroethane. Mixtures,particularly mixtures of an organic solvent such as methanol, ethanol oracetone and water are often desirable. Lower volatility solvents such asdimethyl acetamide or dimethylsulfoxide can also be used. Mixtures ofsolvents, such as 50% methanol and 50% acetone, can also be used, as canmixtures with water as long as the drug is sufficiently soluble to makethe spray-drying process practicable.

Generally, the temperature and flow rate of the drying gas is chosen sothat the droplets containing the adsorbate are dry enough by the timethey reach the wall of the apparatus that they are essentially solid,and so that they form a fine powder and do not stick to the apparatuswall. The actual length of time to achieve this level of dryness dependson the size of the droplets. Droplet sizes generally range from 1 μm to500 μm in diameter, with 5 to 150 μm being more typical. The largesurface-to-volume ratio of the droplets and the large driving force forevaporation of solvent leads to actual drying times of a few seconds orless, and more typically less than 0.1 second. Solidification timesshould be less than 100 seconds, preferably less than a few seconds, andmore preferably less than 1 second. In general, to achieve this rapidsolidification of the solution, it is preferred that the size ofdroplets formed during the spray-drying process are less than about 150μm in diameter. The resultant solid particles thus formed are generallyless than about 150 μm in diameter.

Following solidification, the solid powder typically stays in thespray-drying chamber for about 5 to 60 seconds, further evaporatingsolvent from the solid powder. The final solvent content of the solidadsorbate as it exits the dryer should be low, since this reduces themobility of drug molecules in the adsorbate, thereby improving itsstability. Generally, the solvent content of the adsorbate as it leavesthe spray-drying chamber should be less than 10 wt % and preferably lessthan 2 wt %. Following spray-drying, the adsorbate may be dried in asolvent drier, such as a tray-dryer or a fluidized-bed dryer to removeresidual solvents.

Spray-drying processes and spray-drying equipment are describedgenerally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H.Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984,pages 20-54 to 20-57. More details on spray-drying processes andequipment are reviewed by Marshall “Atomization and Spray-Drying,” 50Chem Eng. Prog. Monogr Series 2 (1954).

As mentioned above, preferred adsorbates of the present invention aremade by processes such as spray-drying that rapidly bring the drug fromthe dissolved state to the solid adsorbed state. Such adsorbates have aunique physical structure and have greater physical stability anddissolution performance relative to those made by processes that slowlyremove solvent.

Another method to produce adsorbates of the present invention comprisingamorphous drug adsorbed to a substrate is a thermal process. Here, thedrug is melted and then coated onto the surface of substrates using, forexample, a twin-screw extruder. In one exemplary technique the drug isfirst uniformly blended with the substrate. The blend may be preparedusing methods well known in the art for obtaining powdered mixtures withhigh content uniformity. For example, the drug and substrate may firstbe independently milled to obtain a small particle size (e.g., less thanabout 100 μm) and then added to a V blender and blended for 20 minutes.This blend may then be milled to break up any agglomerates, and thenblended in a V blender for an additional period of time to obtain auniform preblend of drug and substrate.

This preblend of drug and substrate is fed into a twin screw extruder.The screw configuration and mixing paddles are set so as to maximize thedegree of fill of the screw sections for maximum heat transfer from thebarrel and avoidance of excessive flow restriction. The screwconfiguration is also selected such that there is sufficient mechanicalenergy (i.e., shear) to break apart any aggregated substrate stillremaining after the preblend step and to uniformly mix the drug andsubstrates. The barrel temperature should be ramped from approximatelyroom temperature at the feed area to slightly above the meltingtemperature of the drug in the last barrel zone (discharge end). Thistechnique is applicable for any drug with a melting temperature lowenough to melt in the extruder (<400° C.), and for drugs with acceptablechemical stability at the elevated temperatures. Thermal processes suchas melt-extrusion processes and equipment are described generally inEncyclopedia of Chemical Technology, 4th Edition (John Wiley & Sons,1991).

A processing aid may optionally be blended with such drug/substratemixtures to form a three-component (or more) preblend that is fed to theextruder. One object of such additives is to lower the temperaturerequired for liquification of the drug. Thus, the additive typically hasa melt point below that of the drug and the drug is typically soluble inthe molten additive. The additive may be a volatile material such aswater that evaporates from the composition or it may have a high boilingpoint, such as a mono- or di-glyceride such that it remains part of thecomposition following processing.

Analogous to the solvent processing method described above, it ispreferred to rapidly “quench” the molten material as it exits (isdischarged from) the extruder. Any method that results in rapidsolidification of the drug as a solid adsorbed layer on the substrate issuitable. Exemplary methods are contact with a cooling fluid such as acold gas or liquid. Alternatively, the material may enter a cooled millwhere heat is transferred from the material at the same time as it ismilled into a fine powder with granule sizes from about 100 nm to 100μm.

Alternatively, a solvent, such as water, can be added to the preblendfed to a twin screw extruder. The screw configuration is designed sothat there is sufficient pressure in the extruder to preventvaporization of the solvent at the temperatures required to melt thedrug. When the extrudate exits the extruder, the sudden decrease inpressure causes rapid vaporization of the solvent, leading to rapidcooling and congealing of the adsorbate material. Any residual solventin the composition can be removed using conventional drying technologysuch as a tray drier or a fluidized-bed drier.

Thus, preferred adsorbates of the present invention may be made by anysolvent or thermal process that rapidly solidifies (that is, quenches)the material by solvent removal, precipitation with a nonsolvent orcooling. Such materials, termed “rapidly quenched adsorbates,” havesuperior properties to adsorbates made by other methods.

In particular, when such “rapidly quenched adsorbates” are delivered toan aqueous use environment, they provide enhanced drug concentrations.Specifically, such rapidly quenched adsorbates provide a higher maximumfree drug concentration or a higher maximum total dissolved drugconcentration than that provided by a control, termed a“slow-evaporation control composition,” formed by evaporating thesolvent from a suspension of the same substrate in a solution of drugover a period of 30 minutes or more.

In addition, such rapidly quenched adsorbates may also show improvedphysical stability, slower crystallization rates and superior thermalproperties relative to the slow-evaporation control composition.

The drug/substrate adsorbates resulting from the various preparationtechniques are solid materials comprising about 5 wt % to 90 wt % drug.The materials are typically agglomerates of particles, the agglomerateshaving a mean diameter ranging from 10 nm to 100 μm. The agglomeratestypically retain the fine particulate nature of the starting substrate.In the case of high surface area silicon dioxide, these consist ofbranched chains composed of many particles with mean diameters of about10 to 30 nm, or agglomerates of very small spheres (<10 μm).

For adsorbates in which the substrate has a surface area ofapproximately 200 m²/g, it is believed that for low drug loadings (underabout 12 wt %), the drug is present primarily as drug molecules directlyadsorbed onto the substrate surface. For such high surface areasubstrates, there is sufficient surface area for all drug to be directlyadsorbed to the substrate up to a drug-to-substrate weight ratio ofabout 8. Drug adsorbed onto such substrates can be considered a monolayer. Drug adsorbed in this way is noncrystalline and thus may beconsidered amorphous. However, the interaction of the drug and substratesurface give the drug substantially different physical properties thanbulk amorphous drug alone. At greater drug loadings in the adsorbate, itis believed that the drug forms additional layers of amorphous drug ontop of the initial monolayer. While not wishing to be bound by anyparticular theory, it is believed that the interaction of the thinlayer(s) of the drug with the substrate improves the physical stabilityof the drug by decreasing the mobility of the drug on the substraterelative to the mobility of drug in a bulk amorphous material. This mayresult in improved physical stability by hindering diffusion of drug,and thus inhibiting crystal formation.

As the surface area of the substrate increases, the amount of drug thatcan be incorporated into the adsorbate while maintaining a monolayer (orless) of drug also increases. For example, if the substrate has asurface area of 400 m²/g, the drug loading that leads to a monolayer isapproximately 21 wt %, while if the substrate haspa surface area of 600m²/g, the drug loading can be about 32% while maintaining a monolayer ofdrug on the substrate. Thus, it is desirable to use a substrate with ashigh a surface area as possible to obtain high drug loadings. Suchvalues for the relationship of “drug loading” to substrate surface areaare only approximate and depend on the specific size, shape, andorientation of each specific drug.

The amorphous drug adsorbed to the substrate is in a relatively highenergy state when dosed to an aqueous use environment. While not wishingto be bound by any particular theory or mechanism of action, it isbelieved this high energy state is due to generally reduced drug-druginteractions of the drug adsorbed to the substrate compared withamorphous or crystalline drug alone. The substrate stabilizes thishigh-energy amorphous form of the drug. Thus, when introduced to anaqueous use environment, the drug/substrate adsorbate may provideenhanced aqueous concentration of drug.

The physical nature of this stabilized high-energy state of theamorphous drug may be characterized using IR spectroscopy. Generally,interactions of the drug with the substrate are characterized by a shiftin the IR spectrum to a lower wave number, indicating hydrogen bondingof the drug to the substrate. In addition, the physical nature of theadsorbed drug may be evaluated by techniques such as vapor absorption,thermal calorimetry such as differential scanning colorimetry (DSC), orpowder x-ray diffraction.

The adsorbate may also include optional additional components, inaddition to the processing aids described above, such as surfactants, pHmodifiers, disintegrants, binders, lubricants, etc. These materials mayhelp improve processing, performance, or help in preparing dosage formscontaining the adsorbates, as discussed below.

Preparation of Compositions Containing Adsorbates andConcentration-Enhancing Polymers

In another aspect of the invention, the composition comprises adrug/substrate adsorbate and a concentration-enhancing polymer. Whilethe drug/substrate adsorbate provides enhanced concentration of drug ina use environment relative to amorphous drug alone, the inclusion of aconcentration-enhancing polymer in the composition may improve theobserved enhancement and/or allow for sustaining the enhancedconcentration for a longer period of time.

The compositions of the present invention containingconcentration-enhancing polymers may be prepared through a variety ofmethods The concentration-enhancing polymer may be co-adsorbed onto thesubstrate with the drug, so as to form an amorphous dispersion of drugand polymer adsorbed onto the substrate. Alternatively, theconcentration-enhancing polymer may be combined with the drug/substrateadsorbate in a mixture or a single dosage form. Alternatively, theconcentration-enhancing polymer may be co-administered with theadsorbate.

In one preferred method for combining the adsorbate andconcentration-enhancing polymer, the concentration-enhancing polymer isco-adsorbed with the drug onto the substrate. This results in anamorphous dispersion of drug and polymer adsorbed onto the surface ofthe substrate. The concentration-enhancing polymer may be co-adsorbedwith the drug on the substrate using any method that results in a thinlayer of amorphous drug and polymer adsorbed onto the surface of thesubstrate. The layer may range in thickness from a complete ordiscontinuous layer of drug and polymer molecules adsorbed directly tothe substrate surface, up to a layer of drug and polymer up to athickness of about the size of 5 to 10 polymer or drug molecules. Atleast a major portion of the drug present in the adsorbate is amorphous.Preferably, the drug in the adsorbate is substantially amorphous, andmore preferably, the drug is almost completely amorphous. While thedispersion of drug and polymer adsorbed onto the substrate may havedrug-rich domains and polymer-rich domains, in one embodiment thedispersion is substantially homogeneous, meaning that the amount of thedrug present in drug-rich amorphous domains within the dispersion isless than 20%. Often, for such materials the dispersion is “completelyhomogeneous,” meaning that the amount of drug in drug-rich domains isless than 10%.

One method for adsorbing the concentration-enhancing polymer onto thesubstrate with the drug is to form the adsorbate using a solvent processas described above. In that case, the concentration-enhancing polymerand drug are dissolved in a common solvent to which the substrate hadbeen added. By “common solvent” is meant a solvent capable of dissolvingboth the drug and the concentration-enhancing polymer.

In one exemplary method, the substrate is first added to the commonsolvent and sonicated. The concentration-enhancing polymer is then addedto the solution and dissolved. The drug is then added to the solvent anddissolved. The solvent is then rapidly removed from the resultingsolution of dissolved drug, dissolved polymer and suspended substrate.The resulting particles of adsorbate are then collected and dried.

An alternative method to co-adsorb drug and polymer onto a substrate isusing a thermal process as described above. In one exemplary method,drug, concentration-enhancing polymer, and substrate are preblended andfed to a twin-screw extruder. The extruder is designed to melt the drugand polymer, resulting in adsorption onto the substrate. The compositionis then rapidly cooled to form a rapidly quenched adsorbate, asdescribed above. Additives, such as water, solvents, low-melting-pointsolids, or plasticizers may be added to the preblend to reduce themelting point of the polymer and allow for lower processingtemperatures.

The resulting drug/polymer/substrate adsorbates may comprise from 2 wt %to 90 wt % drug, from 2 to 90 wt % substrate, and from 5 wt % to 95 wt %concentration-enhancing polymer. The mean diameter of thedrug/polymer/substrate adsorbates ranges from 10 nm to 100 μm, and theadsorbates are typically agglomerates of particles having mean diametersof 10 nm to 50 nm.

Alternatively, a drug/substrate adsorbate and a concentration-enhancingpolymer may be mixed together. Mixing processes include physicalprocessing as well as wet- or dry-granulation and coating processes. Anyconventional mixing method may be used. The resulting mixture may be asolid composition comprising the drug/substrate adsorbate andconcentration-enhancing polymer suspended in a matrix, a mixture ofseparate adsorbate particles and concentration-enhancing polymerparticles interspersed with one another, a series of respective layersof adsorbate and concentration-enhancing polymer, or any other mixtureof adsorbate and concentration-enhancing polymer.

For example, mixing methods include convective mixing, shear mixing, ordiffusive mixing. Convective mixing involves moving a relatively largemass of material from one part of a powder bed to another, by means ofblades or paddles, revolving screw, or an inversion of the powder bed.Shear mixing occurs when slip planes are formed in the material to bemixed. Diffusive mixing involves an exchange of position by singleparticles. These mixing processes can be performed using equipment inbatch or continuous mode. Tumbling mixers (e.g., twin-shell) arecommonly used equipment for batch processing. Continuous mixing can beused to improve composition uniformity. Continuous mixers include“in-line” mixers and extruders. Extruders may be single screw ortwin-screw. Twin-screw extruders may turn in the same or oppositedirection.

Milling may also be employed to prepare the compositions of the presentinvention. Milling is the mechanical process of reducing the particlesize of solids (comminution). The most common types of milling equipmentare the rotary cutter, the hammer, the roller and fluid energy mills.Equipment choice depends on the characteristics of the ingredients inthe drug form (e.g., soft, abrasive, or friable). Wet- or dry-millingtechniques can be chosen for several of these processes, also dependingon the characteristics of the ingredients (e.g., drug stability insolvent). The milling process may serve simultaneously as a mixingprocess if the feed materials are heterogeneous. Conventional mixing andmilling processes suitable for use in the present invention arediscussed more fully in Lachman, et al., The Theory and Practice ofIndustrial Pharmacy (3d Ed. 1986).

The components of the compositions of this invention may also becombined by dry- or wet-granulating processes. Theconcentration-enhancing polymer may also be coated onto thedrug/substrate adsorbate using coating techniques known in the art. Forexample, the polymer may be first dissolved into a solvent and thesolution spray-coated onto the adsorbate in a pan-coater or a fluid-bedcoater.

Alternatively, the mixture may be formed by first combining theadsorbate and concentration-enhancing polymer with a matrix, resultingin a mixture of the adsorbate and concentration-enhancing polymersuspended in a matrix.

In addition to the physical mixtures described above, the compositionsof the present invention may constitute any device or collection ofdevices that accomplishes the objective of delivering to the useenvironment both the adsorbate and the concentration-enhancing polymer.The adsorbate and concentration-enhancing polymer may be in differentregions of the composition. For example, in the case of oraladministration to an animal, the dosage form may constitute a layeredtablet wherein one or more layers comprise the adsorbate and one or moreother layers comprise the concentration-enhancing polymer.Alternatively, the dosage form may be a coated tablet wherein the tabletcore comprises the adsorbate and the coating comprises theconcentration-enhancing polymer. The dosage form may also be a capsulewhere the wall of the capsule comprises the concentration-enhancingpolymer and the adsorbate is within the capsule. In addition, theadsorbate and the concentration-enhancing polymer may even be present indifferent dosage forms such as tablets or beads and may be administeredsimultaneously or separately as long as both the adsorbate andconcentration-enhancing polymer are administered in such a way that thedrug and concentration-enhancing polymer can come into contact in theuse environment. When the adsorbate and the concentration-enhancingpolymer are administered separately it is generally preferable todeliver the concentration-enhancing polymer prior to the drug.

The amount of concentration-enhancing polymer relative to the amount ofdrug present in the mixtures of the present invention depends on thedrug and concentration-enhancing polymer and may vary widely from adrug-to-polymer weight ratio of 0.01 to about 20. However, in mostcases, except when the drug dose is quite low, e.g., 25 mg or less, itis preferred that the drug-to-polymer ratio is greater than 0.05 andless than about 5 and often excellent enhancement in drug concentrationor relative bioavailability is observed at drug-to-polymer ratios of 1or less or for some drugs even 0.2 or less. In cases where the drug doseis about 25 mg or less, the drug-to-polymer weight ratio may besignificantly less than 0.05. In general, regardless of the dose,enhancements in drug concentration or relative bioavailability increasewith decreasing drug-to-polymer weight ratio. However, due to thepractical limits of keeping the total mass of a tablet, capsule orsuspension low, it is often desirable to use a relatively highdrug-to-polymer ratio as long as satisfactory results are obtained. Themaximum drug:polymer ratio that yields satisfactory results varies fromdrug to drug and is best determined in the in vitro and/or in vivodissolution tests discussed below.

Concentration-Enhancing Polymers

Concentration-enhancing polymers suitable for use in the various aspectsof the present invention should be pharmaceutically acceptable, andshould have at least some solubility in aqueous solution atphysiologically relevant pHs (e.g. 1-8). Almost any neutral or ionizablepolymer that has an aqueous-solublitity of at least 0.1 mg/mL over atleast a portion of the pH range of 1-8 may be suitable.

It is preferred that the concentration-enhancing polymers be“amphiphilic” in nature, meaning that the polymer has hydrophobic andhydrophilic portions. Amphiphilic polymers are preferred because it isbelieved that such polymers tend to have relatively strong interactionswith the drug and may promote the formation of various types ofpolymer/drug assemblies in solution. A particularly preferred class ofamphiphilic polymers are those that are ionizable, the ionizableportions of such polymers, when ionized, constituting at least a portionof the hydrophilic portions of the polymer. For example, while notwishing to be bound by a particular theory, such polymer/drug assembliesmay comprise hydrophobic drug clusters surrounded by theconcentration-enhancing polymer with the polymer's hydrophobic regionsturned inward towards the drug and the hydrophilic regions of thepolymer turned outward toward the aqueous environment. Alternatively,depending on the specific chemical nature of the drug, the ionizedfunctional groups of the polymer may associate, for example, via ionpairing or hydrogen bonds, with ionic or polar groups of the drug. Inthe case of ionizable polymers, the hydrophilic regions of the polymerwould include the ionized functional groups.

In addition, the repulsion of the like charges of the ionized groups ofsuch polymers (where the polymer is ionizable) may serve to limit thesize of the polymer/drug assemblies to the nanometer or submicron scale.Such drug/concentration-enhancing polymer assemblies in solution maywell resemble charged polymeric micellar-like structures. In any case,regardless of the mechanism of action, the inventors have observed thatsuch amphiphilic polymers, particularly ionizable cellulosic polymerssuch as those listed below, have been shown to interact with drug so asto maintain a higher concentration of drug in an aqueous useenvironment.

One class of polymers suitable for use with the present inventioncomprises neutral non-cellulosic polymers. Exemplary polymers include:vinyl polymers and copolymers having at least one substituent selectedfrom the group comprising hydroxyl, alkylacyloxy, and cyclicamido; vinylcopolymers of at least one hydrophilic, hydroxyl-containing repeat unitand at least one hydrophobic, alkyl- or aryl-containing repeat unit;polyvinyl alcohols that have at least a portion of their repeat units inthe unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinylacetate copolymers; polyvinyl pyrrolidone; polyethylene polyvinylalcohol copolymers, and polyoxyethylene-polyoxypropylene blockcopolymers (also referred to as poloxamers).

Another class of polymers suitable for use with the present inventioncomprises ionizable non-cellulosic polymers. Exemplary polymers include:carboxylic acid-functionalized vinyl polymers, such as the carboxylicacid functionalized polymethacrylates and carboxylic acid functionalizedpolyacrylates such as the EUDRAGITS® manufactured by Rohm Tech Inc., ofMalden, Mass.; amine-functionalized polyacrylates and polymethacrylates;high molecular weight proteins such as gelatin and albumin; andcarboxylic acid functionalized starches such as starch glycolate.

Non-cellulosic polymers that are amphiphilic are copolymers of arelatively hydrophilic and a relatively hydrophobic monomer. Examplesinclude acrylate and methacrylate copolymers. Exemplary commercialgrades of such copolymers include the EUDRAGITS, which are copolymers ofmethacrylates and acrylates.

A preferred class of polymers comprises ionizable and neutral (ornon-ionizable) cellulosic polymers with at least one ester- and/orether-linked substituent in which the polymer has a degree ofsubstitution of at least 0.05 for each substituent. It should be notedthat in the polymer nomenclature used herein, ether-linked substituentsare recited prior to “cellulose” as the moiety attached to the ethergroup; for example, “ethylbenzoic acid cellulose” has ethoxybenzoic acidsubstituents. Analogously, ester-linked substituents are recited after“cellulose” as the carboxylate; for example, “cellulose phthalate” hasone carboxylic acid of each phthalate moiety ester-linked to the polymerand the other carboxylic acid unreacted.

It should also be noted that a polymer name such as “cellulose acetatephthalate” (CAP) refers to any of the family of cellulosic polymers thathave acetate and phthalate substituents attached via ester linkages to asignificant fraction of the cellulosic polymer's hydroxyl groups.Generally, the degree of substitution of each substituent can range from0.05 to 2.9 as long as the other criteria of the polymer are met.“Degree of substitution” refers to the average number of the threehydroxyls per saccharide repeat unit on the cellulose chain that havebeen substituted. For example, if all of the hydroxyls on the cellulosechain have been phthalate substituted, the phthalate degree ofsubstitution is 3. Also included within each polymer family type arecellulosic polymers that have additional substituents added inrelatively small amounts that do not substantially alter the performanceof the polymer.

Amphiphilic cellulosics comprise polymers in which the parent cellulosepolymer has been substituted at any or all of the 3 hydroxyl groupspresent on each saccharide repeat unit with at least one relativelyhydrophobic substituent. Hydrophobic substituents may be essentially anysubstituent that, if substituted to a high enough level or degree ofsubstitution, can render the cellulosic polymer essentially aqueousinsoluble. Examples of hydrophobic substitutents include ether-linkedalkyl groups such as methyl, ethyl, propyl, butyl, etc.; or ester-linkedalkyl groups such as acetate, propionate, butyrate, etc.; and ether-and/or ester-linked aryl groups such as phenyl, benzoate, or phenylate.Hydrophilic regions of the polymer can be either those portions that arerelatively unsubstituted, since the unsubstituted hydroxyls arethemselves relatively hydrophilic, or those regions that are substitutedwith hydrophilic substituents. Hydrophilic substituents include ether-or ester-linked nonionizable groups such as the hydroxy alkylsubstituents hydroxyethyl, hydroxypropyl, and the alkyl ether groupssuch as ethoxyethoxy or methoxyethoxy. Particularly preferredhydrophilic substituents are those that are ether- or ester-linkedionizable groups such as carboxylic acids, thiocarboxylic acids,substituted phenoxy groups, amines, phosphates or sulfonates.

One class of cellulosic polymers comprises neutral polymers, meaningthat the polymers are substantially non-ionizable in aqueous solution.Such polymers contain non-ionizable substituents, which may be eitherether-linked or ester-linked. Exemplary ether-linked non-ionizablesubstituents include: alkyl groups, such as methyl, ethyl, propyl,butyl, etc.; hydroxy alkyl groups such as hydroxymethyl, hydroxyethyl,hydroxypropyl, etc.; and aryl groups such as phenyl. Exemplaryester-linked non-ionizable substituents include: alkyl groups, such asacetate, propionate, butyrate, etc.; and aryl groups such as phenylate.However, when aryl groups are included, the polymer may need to includea sufficient amount of a hydrophilic substituent so that the polymer hasat least some water solubility at any physiologically relevant pH offrom 1 to 8.

Exemplary non-ionizable cellulosic polymers that may be used as thepolymer include: hydroxypropyl methyl cellulose acetate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, andhydroxyethyl ethyl cellulose.

A preferred set of non-ionizable (neutral) cellulosic polymers are thosethat are amphiphilic. Exemplary polymers include hydroxypropyl methylcellulose and hydroxypropyl cellulose acetate, where cellulosic repeatunits that have relatively high numbers of methyl or acetatesubstituents relative to the unsubstituted hydroxyl or hydroxypropylsubstituents constitute hydrophobic regions relative to other repeatunits on the polymer.

A preferred class of cellulosic polymers comprises polymers that are atleast partially ionizable at physiologically relevant pH and include atleast one ionizable substituent, which may be either ether-linked orester-linked. Exemplary ether-linked ionizable substituents include:carboxylic acids, such as acetic acid, propionic acid, benzoic acid,salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid orpropoxybenzoic acid, the various isomers of alkoxyphthalic acid such asethoxyphthalic acid and ethoxyisophthalic acid, the various isomers ofalkoxynicotinic acid such as ethoxynicotinic acid, and the variousisomers of picolinic acid such as ethoxypicolinic acid, etc.;thiocarboxylic acids, such as thioacetic acid; substituted phenoxygroups, such as hydroxyphenoxy, etc.; amines, such as aminoethoxy,diethylaminoethoxy, trimethylaminoethoxy, etc.; phosphates, such asphosphate ethoxy; and sulfonates, such as sulphonate ethoxy. Exemplaryester linked ionizable substituents include: carboxylic acids, such assuccinate, citrate, phthalate, terephthalate, isophthalate,trimellitate, and the various isomers of pyridinedicarboxylic acid,etc.; thiocarboxylic acids, such as thiosuccinate; substituted phenoxygroups, such as amino salicylic acid; amines, such as natural orsynthetic amino acids, such as alanine or phenylalanine; phosphates,such as acetyl phosphate; and sulfonates, such as acetyl sulfonate. Foraromatic-substituted polymers to also have the requisite aqueoussolubility, it is also desirable that sufficient hydrophilic groups suchas hydroxypropyl or carboxylic acid functional groups be attached to thepolymer to render the polymer aqueous soluble at least at pH valueswhere any ionizable groups are ionized. In some cases, the aromaticsubstituent may itself be ionizable, such as phthalate or trimellitatesubstituents.

Exemplary cellulosic polymers that are at least partially ionized atphysiologically relevant pHs include: hydroxypropyl methyl celluloseacetate succinate (HPMCAS), hydroxypropyl methyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulosesuccinate, hydroxyethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxyethyl methyl celluloseacetate succinate, hydroxyethyl methyl cellulose acetate phthalate,carboxyethyl cellulose, ethylcarboxymethyl cellulose (also referred toas carboxymethylethyl cellulose or CMEC), carboxymethyl cellulose,cellulose acetate phthalate (CAP), methyl cellulose acetate phthalate,ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetatephthalate, hydroxypropyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate succinate, hydroxypropylmethyl cellulose acetate succinate phthalate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate (CAT), methyl cellulose acetate trimellitate, ethylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate, hydroxypropyl methyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate succinate, cellulosepropionate trimellitate, cellulose butyrate trimellitate, celluloseacetate terephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate. Of these cellulosic polymers that areat least partially ionized at physiologically relevant pHs, those thatthe inventors have found to be most preferred are HPMCAS, HPMCP, CAP,CAT, carboxyethyl cellulose, carboxymethyl cellulose, and ethylcarboxymethyl cellulose.

Another preferred class of polymers consists of neutralized acidicpolymers. By “neutralized acidic polymer” is meant any acidic polymerfor which a significant fraction of the “acidic moieties” or “acidicsubstituents” have been “neutralized”; that is, exist in theirdeprotonated form By “acidic polymer” is meant any polymer thatpossesses a significant number of acidic moieties. In general, asignificant number of acidic moieties would be greater than or equal toabout 0.1 milliequivalents of acidic moieties per gram of polymer.“Acidic moieties” include any functional groups that are sufficientlyacidic that, in contact with or dissolved in water, can at leastpartially donate a hydrogen cation to water and thus increase thehydrogen-ion concentration. This definition includes any functionalgroup or “substituent,” as it is termed when the functional group iscovalently attached to a polymer, that has a pK_(a) of less than about10. Exemplary classes of functional groups that are included in theabove description include carboxylic acids, thiocarboxylic acids,phosphates, phenolic groups, and sulfonates. Such functional groups maymake up the primary structure of the polymer such as for polyacrylicacid, but more generally are covalently attached to the backbone of theparent polymer and thus are termed “substituents.” Neutralized acidicpolymers are described in more detail in commonly assigned patentapplication U.S. Ser. No. 60/300,256 entitled “PharmaceuticalCompositions of Drugs and Neutralized Acidic Polymers” filed Jun. 22,2001, the relevant disclosure of which is incorporated by reference.

While specific polymers have been discussed as being suitable for use inthe mixtures of the present invention, blends of such polymers may alsobe suitable. Thus the term “concentration-enhancing polymer” is intendedto include blends of polymers in addition to a single species ofpolymer.

Concentration Enhancement

The compositions of the present invention provideconcentration-enhancement relative to a control composition. At aminimum, the compositions of the present invention provideconcentration-enhancement relative to a control comprising crystallinedrug alone. Thus, when the composition is administered to a useenvironment, the composition provides improved drug concentration (asdescribed more fully below) relative to a control consisting of anequivalent amount of crystalline drug alone. Preferably, thecompositions of the present invention provide concentration-enhancementrelative to a control composition containing an equivalent amount ofunadsorbed amorphous drug alone.

For those embodiments of the present invention that compriseconcentration-enhancing polymer, preferably, such compositions provideconcentration-enhancement or bioavailability enhancement relative to acontrol composition comprising an equivalent quantity of drug in thefrom of the adsorbate but free from concentration-enhancing polymer.

As used herein, a “use environment” can be either the in vivoenvironment of the GI tract, subdermal, intranasal, buccal, intrathecal,ocular, intraaural, subcutaneous spaces, vaginal tract, arterial andvenous blood vessels, pulmonary tract or intramuscular tissue of ananimal, such as a mammal and particularly a human, or the in vitroenvironment of a test solution, such as phosphate buffered saline (PBS)or a Model Fasted Duodenal (MFD) solution. Concentration enhancement maybe determined through either in vitro dissolution tests or through invivo tests. It has been determined that enhanced drug concentration inin vitro dissolution tests in Model Fasted Duodenal (MFD) solution orPhosphate Buffered Saline (PBS) is a good indicator of in vivoperformance and bioavailability. An appropriate PBS solution is anaqueous solution comprising 20 mM sodium phosphate (Na₂HPO₄), 47 mMpotassium phosphate (KH₂PO₄), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH6.5 with NaOH. An appropriate MFD solution is the same PBS solutionwherein additionally is present 7.3 mM sodium taurocholic acid and 1.4mM of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. In particular, acomposition may be dissolution-tested by adding it to MFD or PBSsolution and agitating to promote dissolution.

The compositions of the present invention provide in an aqueous useenvironment a concentration versus time Area Under The Curve (AUC), forany period of at least 90 minutes between the time of introduction intothe use environment and about 270 minutes following introduction to theuse environment that is at least 1.25-fold that of at least one of thecontrol compositions. More preferably, the AUC achieved with thecompositions of the present invention are at least 2-fold and morepreferably at least 3-fold that of at least one of the controlcompositions.

A composition of the present invention may also provide a Maximum DrugConcentration (MDC) that is at least 1.25-fold the MDC of at least oneof the control compositions. In other words, if the MDC provided by thecontrol composition is 100 μg/mL, then a composition of the presentinvention provides an MDC of at least 125 μg/mL. More preferably, theMDC of drug achieved with the compositions of the present invention areat least 2-fold, and even more preferably at least 3-fold, that of atleast one of the control compositions.

Alternatively, the compositions of the present invention, when dosedorally to a human or other animal, provide an AUC in drug concentrationin the 3 0 blood plasma or serum that is at least 1.25-fold thatobserved when one of the control compositions is dosed. More preferably,the AUC in the blood plasma or serum is at least 2-fold and morepreferably at least 3-fold that observed when one of the controlcompositions is dosed. Thus, the compositions of the present inventioncan be evaluated in either an in vitro or in vivo test, or both.

A typical test to evaluate enhanced drug concentration can be conductedby (1) adding a sufficient quantity of test composition (e.g., theadsorbate) to a test medium (such as PBS or MFD solution), such that ifall of the drug dissolved, the theoretical concentration of drug wouldexceed the equilibrium concentration of the drug in the test medium by afactor of at least 2; (2) adding an appropriate amount of controlcomposition to an equivalent amount of test medium, and (3) determiningwhether the measured MDC and/or AUC of the test composition in the testmedium is at least 1.25-fold that of the MDC and/or AUC provided by thecontrol composition. In conducting such a dissolution test, the amountof test composition used is an amount such that if all of the drugdissolved, the drug concentration would be at least 2-fold to 100-foldthat of the equilibrium concentration of the drug. The concentration ofdissolved drug is typically measured as a function of time by samplingthe test medium and plotting drug concentration in the test medium vs.time so that the MDC and/or AUC can be ascertained.

To avoid drug particulates which would give an erroneous determinationin in vitro tests, the test solution is centrifuged prior to analysisfor the drug. “Dissolved drug” is typically taken as the material thatremains in the supernatant following centrifugation. Centrifugation istypically carried out in a polypropylene microcentrifuge tube bycentrifuging at 13,000 G for 60 seconds. Other similar centrifugationmethods can be employed and useful results obtained.

Alternatively, the compositions of the present invention provideimproved relative bioavailability. Relative bioavailability of the drugin the compositions of the present invention can be tested in vivo inanimals or humans using conventional methods for making such adetermination. An in vivo test, such as a crossover study, may be usedto determine whether a test composition provides an enhanced relativebioavailability compared with a control composition. In an in vivocrossover study a “test composition” containing the inventivecomposition is dosed to half a group of test subjects and, after anappropriate washout period (e.g., one week) the same subjects are dosedwith a “control composition.” The “control composition” may be any ofthe control compositions described earlier. The other half of the groupis dosed with the control composition first, followed by the testcomposition. The relative bioavailability is measured as the drugconcentration in the blood (serum or plasma) versus time area under thecurve (AUC) determined for the test group divided by the AUC in theblood provided by the control composition. Preferably, this test/controlratio is determined for each subject, and then the ratios are averagedover all subjects in the study. In vivo determinations of AUC can bemade by plotting the serum or plasma concentration of drug along theordinate (y-axis) against time along the abscissa (x-axis).

A preferred embodiment of the invention is one in which the relativebioavailability of the test composition is at least 1.25 relative to atleast one of the control compositions. (That is, the AUC in the bloodprovided by the test composition is at least 1.25-fold the AUC providedby the control composition.) An even more preferred embodiment of theinvention is one in which the relative bioavailability of the testcomposition is at least 2.0 relative to at least one of the controlcompositions and more preferably at least 3. The determination of AUCsis a well-known procedure and is described, for example, in Welling,“Pharmacokinetics Processes and Mathematics,” ACS Monograph 185 (1986).

Improved Drug Stability

In one embodiment, the low-solubility drug in the compositions of thepresent invention has improved physical and/or chemical stabilityrelative to the drug in an appropriate control composition. The controlcomposition may be either (1) the unadsorbed drug in amorphous form(that is, not adsorbed onto a substrate), (2) amorphous drug mixed witha concentration-enhancing polymer, or (3) a solid amorphous dispersionof a drug and concentration-enhancing polymer.

In one aspect, the compositions provide improved physical stability ofthe amorphous drug when adsorbed onto the substrate. As used herein,“physical stability” refers to the rate of change in the drug from theamorphous state to a crystalline state over time in a typical storageenvironment. Drugs in any amorphous state that can exist in either anamorphous or crystalline form tend to crystallize over time, because thecrystalline form of the drug is a lower-energy state than the amorphousform. The physical stability of the drug in the compositions of thepresent invention is improved, meaning that the rate at which the drugchanges from the amorphous to crystalline form is slower in theinventive composition compared with a control composition. It isbelieved that the compositions of the present invention provide improvedphysical stability at least in part because the mobility of the drug onthe substrate is decreased, and hence its ability to crystallize isgreatly inhibited. In addition, the interaction of the drug and thesubstrate surface may tend to hold the drug in an orientation orconformation that differs from that of a crystalline state, therebyreducing the rate of crystallization due to a decrease in the fractionof molecules in a state from which crystallization easily occurs. Thephysical stability of the drug in the composition may be determined byevaluating the change in the physical state (crystalline versusamorphous) of the drug in the inventive composition and comparing therate to the corresponding rate of change provided by a controlcomposition. The rate of change may be measured by any standard physicalmeasurement, such as X-ray diffraction, DSC, or Scanning ElectronMicroscope (“SEM”) analysis. Physically stable compositions of thepresent invention will crystallize at a slower rate than a controlcomposition. Preferably, the rate of crystallization of the drug in theinventive composition is less than 90%, and more preferably less than80%, the rate of crystallization of an appropriate control composition.

In another aspect of the invention, the drug in theinventive-compositions has improved chemical stability compared with anappropriate control composition. As used herein, “chemical stability”refers to the rate of chemical degradation of the drug in a typicalstorage environment. Types of degradation reactions that can occurinclude, but are not limited to hydrolysis, lactonization,esterification, oxidation, reduction, ring cyclization, andtransesterification.

Adsorbing the drug onto an inert substrate can result in improvedchemical stability of the drug by many possible mechanisms. For example,improved chemical stability of the drug may occur by isolating the drugfrom potential reactants, reducing the mobility of the drug, and hence,the rate of reaction of the drug, or both. In such cases the substrateshould be selected such that it preferably does not react with, orcatalyze reactions with the drug or if it does, such a reaction shouldbe acceptably slow. In addition, the substrate should be selected suchthat any degradation products of the substrate itself, if any, are notreactive with the drug. The substrate should also not containunacceptably high levels of impurities that could lead to degradation ofthe drug.

In general, drug degradation may be measured using any conventionalmethod for measuring the purity or potency of drug in a pharmaceuticalcomposition. For example, the amount of active drug present in anadsorbate may be initially measured using high-performance liquidchromatography (HPLC) or other analytical techniques well known in theart Alternatively, the amount of drug initially present may becalculated from the amount of drug present in the solution or mixtureused to form the adsorbate. The potency of the adsorbate is thenmeasured after storage at controlled temperature and humidity conditionsfor an appropriate period of time. A decrease in potency indicates thata chemical reaction has occurred, leading to a decrease in the amount ofactive drug present in the adsorbate, and is an indication of poorchemical stability.

An alternative method used to evaluate chemical stability is to analyzethe rate of increase in the amount of drug degradant(s) in theadsorbate, which would indicate reaction of the drug. An HPLC or otheranalytical technique may be used to determine the concentration of drugdegradant(s) in an adsorbate. The amount of the degradant(s) is measuredbefore and after storage under controlled storage conditions. The amountof increase in the drug degradant(s) may be used to determine the amountof decrease in percent “purity of the drug.” The “percent drug purity”is defined as 100% times the total amount of drug present divided by thetotal amount of drug initially present. Thus, percent drug purity may becalculated by the formula:${{wt}\quad\%\quad{drug}\quad{purity}} = {( \frac{{total}\quad{{amt}.\quad{of}}\quad{drug}{\quad\quad}{present}}{{total}\quad{{amt}.\quad{of}}\quad{drug}\quad{{init}.\quad{present}}} )*100}$

When percent drug purity is calculated from the total amount ofimpurities, “percent drug purity” may be calculated by assuming that,the“total amount of drug initially present,” given in wt %, is equal to 100wt % minus the wt % of total initial impurities, and that “total amountof drug present” is equal to 100 wt % minus the wt % of total impuritiesafter storage, that is, at some later time. This method is equivalent tocalculating “percent drug purity” by the formula:${{wt}\quad\%\quad{drug}\quad{purity}} = {\lbrack {1 - ( \frac{\begin{matrix}{{total}\quad{{amt}.\quad{of}}} \\{{impurities}\quad{present}}\end{matrix}}{\begin{matrix}{{total}\quad{{amt}.\quad{of}}} \\{{drug}\quad{{init}.\quad{present}}}\end{matrix}} )} \rbrack*100}$

The rate at which drug degradation occurs is generally dependent on thestorage conditions. The drug, when formulated as a composition of thepresent invention, should be stable at ambient temperature and humidityconditions (e.g., relative humidities of 20% to 60%) for long periods oftime, such as months or years. However, to expedite testing, the storageconditions may employ elevated temperature and/or humidity to simulatelonger storage times at ambient conditions. The storage time may varyfrom a few days to weeks or months, depending on the reactivity of thedrug and the storage conditions.

A “degree of degradation” of drug following storage may be determined bysubtracting the final drug percent purity (either determined bymeasuring the decrease in drug present or an increase in the amount ofdrug degradants present) from the initial percent purity. For example, acomposition initially containing 100 mg drug and no measurableimpurities would have an initial percent purity of 100 wt %. If, afterstorage, the amount of drug in the composition decreases to 95 mg, thefinal percent purity would be 95 wt % and the “degree of degradation” is5 wt % (100 wt %-95 wt %). Alternatively, if 100 mg of drug substancewere found to initially have 1 mg of impurities present, it would havean initial “percent purity” of 99 wt %. If, after storage, the totalimpurities present had increased to 6 wt %, the final percent puritywould be 94 wt % and the “degree of degradation” would be 5 wt % (99 wt%-94 wt %).

Alternatively, “degree of degradation” can be determined by subtractingthe amount of one or more specific drug degradants initially presentfrom the amount of that specific degradant present after storage. Such ameasure is useful where there are several drug degradants, of which onlyone (or a few) is of concern. The degree of degradation may becalculated on the basis of only those degradants that are of concern,rather than all of the degradants. For example, if a drug initiallycontained a specific degradant at a concentration of 1 wt % and afterstorage the concentration of that degradant was 6 wt %, the degree ofdegradation would be 5 wt % (6 wt %-1 wt %).

A “relative degree of improvement” in chemical stability may bedetermined by taking the ratio of the degree of degradation of the drugin a control composition and the degree of degradation of the drug in atest composition of the present invention under the same storageconditions for the same storage time period. The test composition issimply the drug/substrate adsorbate and (if present in the composition)the concentration-enhancing polymer. The control composition may beeither amorphous drug alone, or when evaluating compositions containinga concentration-enhancing polymer, amorphous drug mixed withconcentration-enhancing polymer, or may be a solid amorphous dispersionof the drug and concentration-enhancing polymer.

For example, where the degree of degradation of a drug in a testcomposition comprised of the drug and substrate is 1 wt %, and thedegree of degradation of a control composition of drug andconcentration-enhancing polymer is 50 wt %, the relative degree ofimprovement is 50 wt %/1 wt %, or 50. For compositions of drugs andsubstrates of this aspect of the present invention, the relative degreeof improvement is at least 1.25. When the drug is particularly unstable,larger relative degrees of improvement may be necessary in order for thechemical stability of the composition to be pharmaceutically acceptableIn such cases, the invention provides greater chemical stability whenthe relative degree of improvement is at least about 2, preferably atleast about 5, and even more preferably at least about 10. In fact, somecompositions may achieve a relative degree of improvement greater than100.

The particular storage conditions and time of storage may be chosen asconvenient depending on the stability of the drug, the particularconcentration-enhancing polymer, and the ratio of drug toconcentration-enhancing polymer. Where the drug is particularlyunstable, or where the composition has a low ratio of drug to polymer,then shorter storage time periods may be used. Where the rate of drugdegradation is linear, the relative degree of improvement will beindependent of the storage time. However, where the rate of drugdegradation is non-linear under controlled storage conditions, thestability test used to compare the test composition with the controlcomposition is preferably chosen such that the degree of degradation issufficiently large that it may be accurately measured. Typically, thetime period is chosen so as to observe a degree of degradation of atleast 0.1 wt % to 0.2 wt %. However, the time period is not so long thatthe ratio of drug to polymer changes substantially. Typically, the timeperiod is such that the observed degree of degradation for the testcomposition is less than 50 wt % and preferably less than 20 wt %. Whenthe rate of drug degradation in the control composition is relativelyslow, the test is preferably conducted over a long enough period of timeunder controlled storage conditions to allow a meaningful comparison ofthe stability of the test composition with the control dispersion.

A stability test which may be used to test whether a composition meetsthe chemical stability criteria described above is storage of the testcomposition and the control composition for six months at 40° C. and 75%RH. A relative degree of improvement may become apparent within ashorter time, such as three to five days, and shorter storage times maybe used for some drugs. When comparing compositions under storageconditions which approximate ambient conditions, e.g., 25° C. and 60%RH, the storage period may need to be from several months up to twoyears.

In addition, it is preferred that the compositions comprising drug andsubstrate result in drug stability such that the drug has a degree ofdegradation of less than about 2 wt %, more preferably less than about0.5 wt %, and most preferably less than about 0.1 wt % when stored at40° C. and 75% RH for six months, or less than about 2 wt %, morepreferably less than about 0.5 wt %, and more preferably less than about0.1 wt %, when stored at 25° C. and 60% RH for one year, or less thanabout 2 wt %, more preferably less than about 0.5 wt %, and morepreferably less than about 0.1 wt %, when stored at ambient conditionsfor two years. Nevertheless, the compositions of the present inventionmay have a degree of degradation that is much greater than the preferredvalues, so long as the test composition achieves the degree ofimprovement relative to a control composition as described above.

The compositions of the present invention are particularly useful wherethe drug degrades in the presence of the concentration-enhancingpolymer. For example, the present invention may be used where the drugis acid-sensitive and it is desired to use an acidicconcentration-enhancing polymer. Often acidic concentration-enhancingpolymers are preferred because such polymers result in superior aqueousconcentration of the drug in the use environment. However, the acidicpolymers may adversely interact with the drug, especially if the drug isdispersed in the acidic polymer. Accordingly, the present inventionsolves this problem by forming an adsorbate to chemically stabilize thedrug. The adsorbate may then be mixed with an acidicconcentration-enhancing polymer, resulting in an adsorbate that hasimproved chemical stability relative to a simple physical mixture of thedrug and concentration-enhancing polymer, or a solid amorphousdispersion of the drug and concentration-enhancing polymer.

Excipients and Dosage Forms

Although the key ingredients present in the compositions of the presentinvention are simply the adsorbate of drug and substrate and theoptional concentration-enhancing polymer(s), the inclusion of otherexcipients in the composition may be useful. These excipients may beutilized with the composition in order to formulate the composition intotablets, capsules, suspensions, powders for suspension, creams,transdermal patches, depots, and the like. In addition, as describedabove, the adsorbate and the optional concentration-enhancing polymermay be mixed with excipients separately to form different beads, orlayers, or coatings, or cores or even separate dosage forms.

One very useful class of excipients is surfactants. Suitable surfactantsinclude fatty acid and alkyl sulfonates; commercial surfactants such asbenzethanium chloride (HYAMINE® 1622, available from Lonza, Inc.,Fairlawn, N.J.); DOCUSATE SODIUM (available from Mallinckrodt Spec.Chem., St. Louis, MO); polyoxyethylene sorbitan fatty acid esters(TWEEN®, available from ICI Americas Inc., Wilmington, Del.); LIPOSORB®P-20 (available from Lipochem Inc., Patterson N.J.); CAPMUL® POE-0(available from Abitec Corp., Janesville, Wis.), and natural surfactantssuch as sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and otherphospholipids and mono- and diglycerides. Such materials canadvantageously be employed to increase the rate of dissolution byfacilitating wetting, thereby increasing the maximum dissolvedconcentration, and also to inhibit crystallization or precipitation ofdrug by interacting with the dissolved drug by mechanisms such ascomplexation, formation of inclusion complexes, formation of micelles oradsorbing to the surface of solid drug. These surfactants may compriseup to 5 wt % of the composition.

The addition of pH modifiers such as acids, bases, or buffers may alsobe beneficial, retarding or enhancing the rate of dissolution of thecomposition, or, alternatively, helping to improve the chemicalstability of the composition.

Other conventional formulation excipients may be employed in thecompositions of this invention, including those excipients well-known inthe art (e.g., as described in Remington's Pharmaceutical Sciences(16^(th) ed. 1980). Generally, excipients such as fillers,disintegrating agents, pigments, binders, lubricants, glidants,flavorants, and so forth may be used for customary purposes and intypical amounts without adversely affecting the properties of thecompositions. These excipients may be utilized after the drug/polymercomposition has been formed, in order to formulate the composition intotablets, capsules, suspensions, powders for suspension, creams,transdermal patches, and the like.

Examples of matrix materials, fillers, or diluents include lactose;mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar,microcrystalline cellulose, powdered cellulose, starch, pregelatinizedstarch, dextrates, dextran, dextrin, dextrose, maltodextrin, calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers suchas polyethylene oxide, and hydroxypropyl methyl cellulose.

Examples of surface active agents include sodium lauryl sulfate andpolysorbate 80.

Examples of drug complexing agents or solubilizers include thepolyethylene glycols, caffeine, xanthene, gentisic acid andcylodextrins.

Examples of disintegrants include sodium starch glycolate, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellosesodium, crospovidone (polyvinylpolypyrrolidone), methyl cellulose,microcrystalline cellulose, powdered cellulose, starch, pregelatinizedstarch, and sodium alginate.

Examples of tablet binders include acacia, alginic acid, carbomer,carboxymethyl cellulose sodium, dextrin, ethylcellulose, gelatin, guargum, hydrogenatetd vegetable oil, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, liquidglucose, maltodextrin, polymethacrylates, povidone, pregelatinizedstarch, sodium alginate, starch, sucrose, tragacanth, and zein.

Examples of lubricants include calcium stearate, glyceryl monostearate,glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil,magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate,sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, andzinc stearate.

Examples of glidants include silicon dioxide, talc and cornstarch.

Compositions of this invention may be used in a wide variety of dosageforms for administration of drugs. Exemplary dosage forms are powders orgranules that may be taken orally either dry or reconstituted byaddition of water to form a paste, slurry, suspension or solution;tablets; capsules; multiparticulates; and pills. Various additives maybe mixed, ground, or granulated with the compositions of this inventionto form a material suitable for the above dosage forms.

In some cases, the overall dosage form or particles, granules or beadsthat make up the dosage form may have superior performance if coatedwith an enteric polymer to prevent or retard dissolution until thedosage form leaves the stomach. Exemplary enteric coating materialsinclude HPMCAS, HPMCP, CAP, CAT, carboxymethylethyl cellulose,carboxylic acid-functionalized polymethacrylates, and carboxylicacid-functionalized polyacrylates.

Compositions of this invention may be administered in a controlledrelease dosage form. In one such dosage form, the composition of theadsorbate and optional concentration-enhancing polymer is incorporatedinto an erodible polymeric matrix device. By an erodible matrix is meantaqueous-erodible or water-swellable or aqueous-soluble in the sense ofbeing either erodible or swellable or dissolvable in pure water orrequiring the presence of an acid or base to ionize the polymeric matrixsufficiently to cause erosion or dissolution. When contacted with theaqueous environment of use, the erodible polymeric matrix imbibes waterand forms an aqueous-swollen gel or “matrix” that entraps the mixture ofadsorbate and optional concentration-enhancing polymer. Theaqueous-swollen matrix gradually erodes, swells, disintegrates ordissolves in the environment of use, thereby controlling the release ofthe drug mixture to the environment of use.

Alternatively, the compositions of the present invention may beadministered by or incorporated into a non-erodible matrix device.

Alternatively, the drug mixture of the invention may be delivered usinga coated osmotic controlled release dosage form. This dosage form hastwo components: (a) the core which contains an osmotic agent and theadsorbate; and (b) a coating surrounding the core, the coatingcontrolling the influx of water to the core from an aqueous environmentof use so as to cause drug release by extrusion of some or all of thecore to the environment of use. The osmotic agent contained in the coreof this device may be an aqueous-swellable hydrophilic polymer,hydrogel, osmogen, or osmagent. The coating is preferably polymeric,aqueous-permeable, and has at least one delivery port.

The optional concentration-enhancing polymer may be either mixed withthe adsorbate (as described above) or be in a separate region of thecore or it may be applied as all or part of the coating that controlsthe influx of water, or as a separate coating.

Alternatively, the drug mixture of the invention may be delivered via acoated hydrogel controlled release dosage form having three components:(a) a drug-containing composition containing the adsorbate, (b) awater-swellable composition wherein the water-swellable composition isin a separate region within a core formed by the drug-containingcomposition and the water-swellable composition, and (c) a coatingaround the core that is water-permeable, and has at least one deliveryport therethrough. In use, the core imbibes water through the coating,swelling the water-swellable composition and increasing the pressurewithin the core, and fluidizing the drug-containing composition. Becausethe coating remains intact, the drug-containing composition is extrudedout of the delivery port into an environment of use. The optionalconcentration-enhancing polymer may be delivered in a separate dosageform, may be mixed with the adsorbate (as described above) and bepresent in the drug-containing composition, may be included in thewater-swellable composition, may be included in a separate layer withinthe core, or may constitute all or part of a coating applied to thedosage form, or as a separate coating.

In one embodiment, the compositions of the present invention may beco-administered, meaning that the adsorbate can be administeredseparately from, but within the same general time frame as, theconcentration-enhancing polymer. Thus, an adsorbate can, for example, beadministered in its own dosage form which is taken at approximately thesame time as the concentration-enhancing polymer which is in a separatedosage form. If administered separately, it is generally preferred toadminister both the adsorbate and the concentration-enhancing polymerwithin 60 minutes of each other, so that the two are present together inthe environment of use. When not administered simultaneously, theconcentration-enhancing polymer is preferably administered prior to theadsorbate.

In addition to the above additives or excipients, use of anyconventional materials and procedures for preparation of suitable dosageforms using the compositions of this invention known by those skilled inthe art are potentially useful.

Other features and embodiments of the invention will become apparentfrom the following examples which are given for illustration of theinvention rather than for limiting its intended scope.

EXAMPLES Example 1

A drug/substrate adsorbate comprising quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl)-2(S),7-dihydroxy-7-methyl-octyl]amide (“Drug 1”) and zinc oxide (thesubstrate) was prepared as follows. Drug 1 (0.15 wt %) was dissolved ina suspension of zinc oxide (NanoTek®, 30 to 60 nm, surface area of 15 to45 m²/gm, 1.33 wt %) in methanol (a solvent for Drug 1) to form a milkysuspension. This suspension was pumped into a “mini” spray-dryingapparatus via a syringe pump at a rate of 1.3 mL/min. A high frequencyvibrational device (Whisper 700—Sound Natural) was attached to thesyringe to maintain a homogeneous suspension while the adsorbate wasbeing formed. The spray solution was metered using a Cole Parmer 74900series rate-controlling syringe pump. The solution was pumped into aSpraying Systems Co. two-fluid nozzle, model number SU1A, with nitrogenas the atomizing gas. The nitrogen was pressurized and heated to atemperature of 100° C. at a flow rate of about 1 scfm. The solution wassprayed from the top of an 11-cm diameter stainless steel chamber. Theresulting drug/substrate adsorbate was collected on Whatman® 1 filterpaper at a yield of about 53%, dried under vacuum, and stored in adessicator. After drying, the Example 1 adsorbate contained 10 wt % Drug1 and 90 wt % ZnO.

Control 1A: Control 1A was crystalline Drug 1 alone.

Example 2

The drug/substrate adsorbate of Example 1 and the crystalline drug ofControl 1A were evaluated in an in vitro dissolution test using amicrocentrifuge method. In this test, 18 mg of the adsorbate of Example1, or 1.8 mg of Control 1A, was added to a microcentrifuge tube. Thetubes were placed in a 37° C. temperature-controlled chamber, and 1.8 mLphosphate buffered saline (PBS) at pH 6.5 and 290 mOsm/kg was added. Thesolutions were quickly mixed using a vortex mixer for about 60 seconds,and then centrifuged at 13,000 G at 37° C. for minute. The resultingsupernatant solution was then sampled and diluted 1:5 (by volume) withmethanol. Diluted samples were analyzed by high-perfomance liquidchromatography (HPLC) at a UV absorbance of 245 nm using a PhenomenexKromasil C₄ column and a mobile phase of 45% (0.2% H₃PO₄)/55%acetonitrile. After sampling, the contents of the tubes were mixed onthe vortex mixer and allowed to stand undisturbed at 37° C. until thenext sample was taken. Samples were collected at 4, 10, 20, 40, 90, and1200 minutes. the concentrations of drug obtained in these samples areshown in Table 2A. Results for Example 1 are averages of two tests,while results for Control 1A are averages of 6 tests. TABLE 2A Drug 1Time Concentration AUC Example (min) (μg/mL) (min * μg/mL) 1 0 0 0 4 9862,000 10 1098 8,200 20 1028 18,900 40 860 37,700 90 426 69,900 1200 404530,500 Control 1A 0 0 0 4 254 510 10 298 2,200 20 306 5,200 40 30211,300 90 329 27,000 180 325 56,500 1200 319 385,000

The results of these tests are summarized in Table 2B, which shows themaximum concentration of Drug 1 in solution during the first 90 minutesof the test (C_(max,90)), the area under the aqueous concentrationversus time curve after 90 minutes (AUC₉₀). TABLE 2B Drug 1 Conc. in theAdsorbate C_(max,90) AUC₉₀ Example Substrate (wt %) (μg/mL) (min *μg/mL) 1 zinc oxide 10 1100 69,900 Control 1A None — 329 27,000 4CAB-O-SIL 25 901 77,700 M-5PThese results show that the C_(max,90) provided by the adsorbate ofExample 1 was 3.3-fold that of the crystalline Control 1A, while theAUC₉₀ was 2.6-fold that of the Control 1A.Control 1 B; Control 1 B was amorphous Drug 1 alone, prepared by spraydrying a solution consisting of 2.02 wt % Drug 1 and 97.98 wt % methanolusing the procedures outlined in Example 1 except that the concentrationof Drug 1 in the methanol solution was 2.02 wt %, and no vibrationaldevice was required. The resulting amorphous Drug 1 was collected at ayield of about 43%, dried under vacuum, and stored in a dessicator.

Example 3

The stability of Example 1 adsorbate was evaluated in an acceleratedstorage test. The adsorbate was stored under elevated temperature andhumidity conditions to increase the rate of physical changes occurringin the material in order to simulate a longer storage interval in atypical storage environment. Samples of the adsorbate and Control 1Bwere stored at 40° C./75% relative humidity (RH). Samples were analyzedusing a powder X-ray diffraction (PXRD) technique using a Bruker AXS D8Advance diffractometer as follows. The X-ray tube (KCu, 1.54184 Å) wasoperated at a voltage of 45 kV and a current of 40 mA with the beamfocused through a Gobel mirror and a series of slits into a line focus.Diffractograms were typically collected over the 2□ range of 4° to 40°with a step size of 0.02°/step. Data were collected for a minimum timeof 2.4 sec/step. Scans were obtained by holding the tube at a constantangle (to keep the illuminated area of the sample constant) and scanninga scintillation-counter detector fitted with a thin film collimatorthrough 20□. All standards and samples were spun in the □ plane at arate of 30 rpm to minimize orientation effects. Sample cups of either

-   (1) standard Bruker plastic cups that were 1 mm deep (with deeper    grooves), or-   (2) zero background cups with a depth of 0.5 mm made by fixing    Si(51 1) wafers in the bottoms of standard Bruker cups. Standards    (150 to 200 mg) were prepared and leveled into cups by chopping the    powder into place with light pressure from a spatula and scraping    the excess away.

The results of these tests showed that Drug 1 in the adsorbate ofExample 1 did not crystallize after being stored for 4 weeks at 40°C./75% RH. Control 1B showed significant crystallization after beingstored for 1 week at the same conditions. Thus, the composition of thepresent invention had improved physical stability over that of thecontrol.

Example 4

A drug/substrate adsorbate of Drug 1 was prepared using fumed silicafrom Cabot Corporation sold as CAB-O-SIL M-5P as a substrate. Drug 1 wasfirst mixed with CAB-O-SIL M-5P (surface area of about 200 m²/gm) inmethanol to form a suspension. Drug 1 was then dissolved in thissuspension such that the suspension comprised 0.25 wt % Drug 1, 0.74 wt% CAB-O-SIL M-5P, and 99.01 wt % methanol. The syringe, containing a2-cm stir bar, was placed near a stir plate to maintain a homogeneoussuspension. This suspension was pumped into a “mini” spray-dryingapparatus via a syringe pump at a rate of 1.3 mL/min. The spray solutionwas metered using a Cole Parmer 74900 series rate-controlling syringepump. The solution was pumped into a Spraying Systems Co. two-fluidnozzle, model number SU1A, with nitrogen as the atomizing gas. Thenitrogen was pressurized and heated to a temperature of 100° C. with aflow rate of 1.08 standard cubic feet per minute (scfm). The resultingdrug/substrate adsorbate was collected on Whatman® 1 filter paper at ayield of about 53%, dried under vacuum, and stored at −20° C. Afterdrying, the adsorbate of Example 4 contained 25 wt % Drug 1 and 75 wt %CAB-O-SIL M-5P.

Example 5

The adsorbate of Example 4 was evaluated in an in vitro dissolution testusing the procedures outlined in Example 2, except that 7.2 mg of theadsorbate of Example 4 was used. The concentrations of drug obtained inthese samples are shown in Table 5A. TABLE 5A Drug 1 Time ConcentrationAUC Example (min) (μg/mL) (min * μg/mL) 4 0 0 0 4 828 1,660 10 868 6,75020 877 15,500 40 883 33,100 90 901 77,700 1200 398 799,000The results of this test are summarized in Table 2B, and show that theC_(max,90) provided by the adsorbate of Example 4 was 2.7-fold that ofthe crystalline control (Control 1A), while the AUC₉₀ for the adsorbatewas 2.9-fold that of Control 1A.

Example 6

A drug/substrate adsorbate comprising [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (“Drug 2”) and CAB-O-SIL M-5P was prepared by firstadding CAB-O-SIL M-5P to acetone and then sonicating the mixture using aFisher Scientific SF15 sonicator for 10 minutes to ensure fullsuspension and homogeneity. Drug 2 was then dissolved in this suspensionresulting in a mixture that contained 0.18 wt % Drug 2, 1.6 wt %CAB-O-SIL M-5P, and 98.2 wt % acetone. This suspension was then pumpedinto a “mini” spray-drying apparatus via a Cole Parmer 74900 seriesrate-controlling syringe pump at a rate of 1.0 mL/min. The spray-dryingapparatus used a Spraying Systems Co. two-fluid nozzle, model numberSU1A, with nitrogen as the atomizing gas. The nitrogen was pressurizedand heated to a temperature of 110° C. and had a flow rate of about 1scfm. The suspension was sprayed from the top of an 11-cm diameterstainless steel chamber. The resulting solid amorphous adsorbate wascollected on Whatman® 1 filter paper at a yield of about 46%, driedunder vacuum, and stored in a dessicator. After drying, the Example 6adsorbate contained 10 wt % Drug 2 and 90 wt % CAB-O-SIL M-5P.

Control 2A: Control 2A was crystalline Drug 2 without the substrate.

Control 2B: Control 2B was amorphous Drug 2 without the substrate.

Example 7

The adsorbate of Example 6 and the crystalline drug of Control 2A wereevaluated in an in vitro dissolution test using a microcentrifuge methodas in Example 2. In this test, 9 mg of the adsorbate of Example 6, or1.8 mg of Control 2A, was added to a microcentrifuge tube. The tubeswere placed in a 37° C. temperature-controlled chamber, and 1.8 mL of0.5 wt % MFD solution at pH 6.5 and 290 mOsm/kg was added. The sampleswere quickly mixed using a vortex mixer for about 60 seconds. Thesamples were centrifuged at 13,000 G at 37° C. for 1 minute. Theresulting supernatant solution was then sampled and diluted 1:5 (byvolume) with methanol. Diluted samples were analyzed by HPLC at a UVabsorbance of 256 nm using a Waters Symmetry C₈ column and a mobilephase consisting of 15% (0.2% H₃PO₄)/85% methanol. The contents of thetubes were mixed on the vortex mixer and allowed to stand undisturbed at37° C. until the next sample was taken. Samples were collected at 4, 10,20, 40, 90, and 1200 minutes. The concentrations of drug obtained inthese samples are shown in Table 7A. TABLE 7A Drug 2 Time ConcentrationAUC Example (min) (μg/mL) (min * μg/mL) 6 0 0 0 4 89 180 10 63 640 20 291,100 40 <1 1,400 90 <1 1,400 1200 <1 1,400 Control 2A 0 0 0 4 3 6 10 221 20 8 71 40 4 190 90 11 570 1200 15 14,700

The results of this test are summarized in Table 7B and show that theadsorbate of Example 6 provided a C_(max,90) value that was at least11-fold that of the Control 2A and an AUC₉₀ that was 2.5-fold that ofthe Control 2A. TABLE 7B Drug 2 Conc. In the Adsorbate C_(max,90) AUC₉₀Example Substrate (wt %) (μg/mL) (min * μg/mL) 6 CAB-O-SIL 10 89 1400M-5P Control 2A none — 11 570 8 CAB-O-SIL 15 62 790 M-5P 9 CAB-O-SIL 25186 8700 M-5P

Example 8

A drug/substrate adsorbate was prepared following the procedure ofExample 6 except that the suspension consisted of 0.27 wt % Drug 2, 1.52wt % CAB-O-SIL M-5P, and 98.2 wt % acetone. After drying, the Example 9adsorbate contained 15 wt % Drug 2 and 85 wt % CAB-O-SIL M-5P.

Example 9

A drug/substrate adsorbate of Drug 2 and CAB-O-SIL M-5P, was preparedusing the procedure outlined in Example 6 except that the suspensionconsisted of 0.56 wt % Drug 2, 1.68 wt % CAB-O-SIL M-5P, and 97.8 wt %acetone, and was pumped via a syringe pump at a rate of 1.2 ml/min. Thenitrogen gas was heated to a temperature of 100° C. at a flow rate ofabout 1 scfm. After drying, the Example 9 adsorbate contained 25 wt %Drug 2 and 75 wt % CAB-O-SIL M-5P.

Example 10

The adsorbates of Example 8 and Example 9 were evaluated in an in vitrodissolution test as in Example 7. In this test, 12 mg of the adsorbateof Example 8 or 7.2 mg of adsorbate of Example 9, was added to amicrocentrifuge tube, along with 1.8 mL of a 0.5 wt % MFD solution at pH6.5 and sampled as described in Example 7. The concentrations of drugobtained in this samples are shown in Table 10 A. TABLE 10A Drug 2 TimeConcentration AUC Example (min) (μg/mL) (min * μg/mL) 8 0 0 0 4 62 13010 33 410 20 14 650 40 <1 790 90 <1 790 1200 <1 790 9 0 0 0 4 158 300 10162 1,300 20 105 2,900 40 49 5,130 90 25 8,720 1200 12 45,600The results of this test are summarized in Table 7B and show that theC_(max,90) for the adsorbate of Example 8 was 5.6-fold that of thecrystalline drug alone (Control 2A), while the AUC₉₀ was 1.4-fold thatof the control. The adsorbate of Example 9 provided a C_(max,90) valuethat was 16.9-fold that of the control and an AUC₉₀ that was 15.3-foldof Control 2A.

Example 11

The adsorbate of Example 9 and the crystalline drug of Control 2A wereevaluated using a nuclear magnetic resonance (NMR) test. In this test,0.690 mg of the adsorbate of Example 9, or 0.174 mg of Control 2, wasadded to a microcentrifuge tube. The tubes were placed in a 37° C.temperature-controlled chamber, and 1.7 mL for Example 9, or 1.8 mL forControl 2A, of 2 wt % deuterated MFD solution (d-MFD) at pH 6.5, 37° C.,and 290 mOsm/kg was added. The samples were quickly mixed using a vortexmixer for 60 seconds. The samples were allowed to sit for 30 minutes inthe 37° C. warm box before centrifugin at 13,000 G for 1 minute. Thesupernatant was then carefully transferred to an 8 mm glass NMR tube forExample 9. For Control 2A, the pellet was resuspended using Pasteurpipets and the sample was then carefully transferred to an NMR tube. Aninternal standard solution of trifluoroacetic acid (TFA) was added tothe tubes to give a concentration of 0.2762 mM ¹⁹F for Example 9 or0.3565 mM ¹⁹F Control 2A.

Fluorine spectra of the sample were recorded at 282.327 MHz on a VarianGemini 2000, 300 MHz NMR equipped with a Nalorac 8 mm indirect detectionprobe. The sample temperature was maintained at 37° C. in the probe andthe spectra acquired using a 90° pulse width and 20 second pulse delay(delay >5*t₁ drug or standard). Drug resonances were integrated relativeto the internal standard peak and the drug concentration determined. Thegiven experiment time was calculated from the time the solvent was addedto the solid sample until half of the time the spectrum had beenacquired by the NMR. For example, when the spectra has been recorded for2 hours after the sample was equilibrated for 30 minutes the time listedfor the NMR result is 90 minutes.

Fluorine NMR data was collected for the appropriate number of scans togive good signal to noise, which gave an approximate timepoint of 90minutes for Example 9 or 60 minutes for Control 2A. Acquisitionparameters included an acquisition time of 0.788 seconds and a delaytime of 19.2 seconds for a total relaxation time of 20 seconds to avoiduse of fractional intensity calculations. Peaks were integrated andcorrected for number of molecular fluorines in internal standard todetermine the concentration of Drug 2.

The results of this test are summarized in Table 11, which shows theconcentration of Drug 2 in solution for Example 9 and Control 2A. Notethat no dissolved drug was detected at 60 minutes or 240 minutes forControl 2A. After equilibration for 3 days, the dissolved Drug 2concentration for Control 2A was 13 μgA/mL (“μgA” refers to μg of activedrug). Thus, the adsorbate of Example 9 provided an enhanced dissolveddrug concentration over that of the control. TABLE 11 Drug 2 DissolvedConc. Drug 2 in the Concentration Adsorbate (μgA/mL) Example Substrate(wt %) (for NMR)  9 CAB-O-SIL 25 59 M-5P (90 minutes) Control 2A none/ — 0 crystalline (60 minutes and 240 minutes) 13 CAB-O-SIL 25 41 EH-5P (90minutes) 14 CAB-O-SIL 25 42 C-90 (90 minutes)

Example 12

Samples of the adsorbate of Example 9 were assessed for physicalstability by storing them for 12 weeks at 50° C./75% RH. The samplesshowed no crystallinity, indicating the adsorbate was physically stable.

Example 13

For Example 13, a drug/substrate adsorbate comprising Drug 2 andCAB-O-SIL EH-5 (Cabot Corp.) (having a surface area of about 380 m²/g)was prepared as described in Example 6 but with a suspension consistingof 0.5 wt % Drug 2, 1.5 wt % CAB-O-SIL EH-5, and 98 wt % acetone. Thesolution was pumped via a syringe pump at a rate of 1.17 ml/min. Thenitrogen gas was heated to a temperature of 100° C. at a flow rate ofabout 1 scfm. After drying, Example 13 adsorbate contained 25 wt % Drug2 and 75 wt % CAB-O-SIL EH-5.

Example 14

For Example 14, a drug/substrate adsorbate was made from Drug 2 andCAB-O-SIL L-90 (surface area of 90 m²/g), spray-dried as described inExample 13. After drying, Example 14 adsorbate contained 25 wt % Drug 2and 75 wt % CAB-O-SIL L-90.

Example 15

The adsorbates of Example 13 and Example 14 were evaluated using thenuclear magnetic resonance (NMR) test described in Example 11. Theresults of these tests are summarized in Table 11, which shows theconcentration of Drug 2 in solution for Example 13 and Example 14, aswell as Control 2A.

These results show that the adsorbate of Examples 13 and 14 providedenhanced Drug 2 concentrations relative to the crystalline Control 2A.

Example 16

The adsorbates of Examples 6, 9, 13, and 14 were analyzed by Fouriertransform infrared (FTIR) spectroscopy to characterize the interactionof Drug 2 and the silicon dioxide substrate. The analysis was performedusing a Nicolet Nexus 670 spectrometer using the Smart MIRacle accessoryfor single reflection attenuated total reflection (ATR). Approximately5-10 mg of sample was added to the sample compartment for themeasurement of a spectrum. The detector was a nitrogen cooledmercury-cadmium-telluride (MCT) detector. Spectra were averages of 64scans with 1 cm⁻¹ resolution. Comparison was made to an FTIR spectrum ofamorphous drug alone (Control 2B).

The spectrum of Control 2B showed a Drug 2 carbonyl (C═O stretch)vibration peak at 1700 cm⁻¹. This is the characteristic vibration energyfor interactions of the carbonyl group of Drug 2 in amorphous Drug 2alone.

Example 6 was a Drug 2/CAB-O-SIL M-5P adsorbate, wherein the Drug 2concentration was 10 wt % and the substrate surface area was about 200m²/g. The FTIR spectrum of the adsorbate of Example 6 showed a shift inthe carbonyl peak to 1680 cm⁻¹, indicating the carbonyl groups of Drug 2were hydrogen bonding with the hydroxyl groups terminating the SiO₂surface of the substrate. The data show that all of the drug in theadsorbate was hydrogen bonding with the substrate, suggesting the drugwas adsorbed as a monolayer on the substrate.

Example 9 was a 25 wt % Drug 2 adsorbate on CAB-O-SIL M-5P (with asurface of about 200 m²/g). The FTIR spectrum of the adsorbate ofExample 9 showed the drug to exist in two different amorphous states.The spectrum showed evidence of C═O stretch vibrations at both 1700 cm⁻¹and 1680 cm⁻¹, indicating that a portion of the drug in the adsorbatewas hydrogen bonding to the substrate, while the remainder of the drugwas in an amorphous drug environment.

Similar results were observed for the adsorbate of Example 13, which wasa 25 wt % Drug 2 adsorbate on CAB-O-SIL EH-5 (with a surface area ofabout 380 m²/g). The FTIR spectrum of the adsorbate of Example 13 showeda larger fraction of the drug was hydrogen bonding with the substratethan for the adsorbate of Example 9. This is because the surface area ofthe CAB-O-SIL EH-5 used for Example 13 was larger than that for Example9, allowing a higher fraction of the drug to be bound to the substratein a monolayer.

The FTIR spectrum for the adsorbate of Example 14 (a 25 wt % Drug 2adsorbate on CAB-O-SIL L-90 with a surface area of about 90 m²/g) alsoshowed the drug exists as two amorphous forms. For the adsorbate ofExample 14, a smaller fraction of the drug was hydrogen bonding with thesubstrate than for the adsorbates of Example 9 and Example 13 due to thelower surface area of the substrate in Example 14.

Example 17

A drug/substrate adsorbate of5-(2-(4-(3-benzisothiazolyl)-piperazinyl)ethyl-6-chlorooxindole (“Drug3”) and CAB-O-SIL M-5P was prepared by first mixing CAB-O-SIL M-5P in asolvent, sonicating, and then adding Drug 3. The solution consisted of0.194 wt % Drug 3, 0.584 wt % CAB-O-SIL, and 99.22 wt % 7/3 (by weight)methanol/tetrahydrofuran. The CAB-O-SIL was added to the solvent andthen sonicated using a Fisher Scientific SF15 sonicator for 10 minutesto ensure full suspension and homogeneity. Then Drug 3 was dissolved inthe suspension with additional sonication. The suspension was spraydried by pumping it via a syringe pump at a rate of 0.75 ml/min into aspray-drying apparatus using a Spraying Systems Co. two-fluid nozzle,model number Su1A, with nitrogen as the atomizing gas. The nitrogen waspressurized and headed to a temperature of 120° C. at a flow rate ofabout 1 scfm. The solution was sprayed from the top of an 11 centimeterdiameter stainless steel chamber. The resulting drug/substrate adsorbatewas collected on Whatman® filter paper at a yield of about 61%, driedunder vacuum, and stored in a dessicator. After drying, Example 17adsorbate contained 25 wt % Drug 3 and 75 wt % CAB-O-SIL M-5P.

Control 3A: Contol consisted of the crystalline form of Drug 3 without asubstrate.

Example 18

The adsorbate of Example 17 was evaluated in an in vitro dissolutiontest as in Example 2 using 1.44 mg of the adsorbate of Example 20, or0.36 mg of crystalline Drug 3 (Control 3) in a microcentrifuge tube with1.8 ml of 0.5 wt % MFD solution. Samples were analyzed by HPLC at a UVabsorbance of 254 nm using a Phenomex ODS 20 column and a mobile phaseconsisting of 60% 0.02 M kh₂PO₄(pH 3.0)/40% acetonitrile. Theconcentrations of drug obtained in these samples are shown in Table 18A.TABLE 18A Drug 3 Time Concentration AUC Example (min) (μgA/mL) (min *μg/mL) 17 0 0 0 4 7 10 10 5 50 20 4 100 40 4 180 90 3 370 1200 3 3700Control 3A 0 0 0 4 3 10 10 2 20 20 1 30 40 2 60 90 2 150 1200 5 3900

The results of this test are summarized in Table 18B and show that theadsorbate of Example 17 provided a C_(max,90) value that was 2.7-foldthat of the crystalline Control 3A, and an AUC₉₀ that was 2.1-fold thatof the Control 3A. TABLE 18B Drug 3 Conc. in the Adsorbate C_(max,90)AUC₉₀ Example Substrate (wt %) (μg/mL) (min * μg/mL) 17 CAB-O-SIL 25 8320 M-5P Control 3A none — 3 150

Example 19

The adsorbate of Example 17 was stored at 40□C. and 75% relativehumidity for 6 weeks. The aged sample was analyzed by PXRD and a smallamount of crystalline drug was detected, indicating the adsorbate hadexcellent physical stability. Attempts were made to form amorphous Drug3 using a spray-drying process, but amorphous Drug 3 could not be formeddue to rapid crystallization.

Example 20

The adsorbate of Example ⁺17 was analyzed by FTIR as described inExample 16. The Example 17 adsorbate showed hydrogen bonding of Drug 3onto the SiO₂ surface. The carbonyl bond at 1730 cm⁻¹ shifted to lowerenergies at 1710 cm⁻¹ when the drug was hydrogen bonded to the SiO₂surface.

This suggests a monolayer of Drug 3 had adsorbed to the substrate.

Example 21

A drug/substrate adsorbate of Indomethacin (“Drug 4”) was produced usingthe same equipment and techniques as described in Example 6. To form theadsorbate of Example 21, 150 mg of Drug 4 was added to a suspension of450.2 mg Silicon Dioxide (Cab-O-Sil M-5P) in 60 g acetone. Thehomogeneous suspension was pumped into the mini spray drier at a rate of1.3 mLs/min. The nitrogen gas used to atomize the solution was at atemperature of 105° C. and a flow rate of 1 scfm. The yield of theprocess was about 63%. The adsorbate was dried under vacuum, and storedin a dessicator. After drying, the adsorbate of Example 21 contained 25wt % Drug 4 and 75 wt % CAB-O-SIL M-SP.

Control 4: Control 4 was crystalline Drug 4 alone.

Example 22

The adsorbate of Example 21 was evaluated in an in vitro dissolutiontest as described in Example 2 for Drug 1. In this test, 36 mg of theadsorbate of Example 21, or 9 mg of Control 4, was added to themicrocentrifuge tubes used in the test. Samples were analyzed by HPLC ata UV absorbance of 254 nm using an Alltech platinum EPS 1A8 column and amobile phase consisting of 40% 0.02 M KH₂PO₄(pH 4.5)/10%acetonitrile/50% methanol. Samples for this test were collected at 4,10, 20, 40, and 90 minutes. The concentrations of Drug 4 obtained inthese samples are shown in Table 22A. TABLE 22A Drug 4 TimeConcentration AUC Example (min) (μgA/mL) (min * μg/mL) 21 0 0 0 4 35207,100 10 2370 24,700 20 1840 45,700 40 1670 80,800 90 1570 161,500 12001030 1,605,000 Control 4 0 0 0 4 320 630 10 340 2,600 20 610 7,300 40460 8,100 90 480 41,700 1200 400 527,700

The results of this test are summarized in Table 22B. TABLE 22B Drug 4Conc. Adsorbate in the AUC₉₀ Formation Adsorbate C_(max,90) (min *Example Process Substrate (wt %) (μgA/mL) μg/mL) 21 spray- CAB-O-SIL 253520 161,500 dried M-5P Control 4 — None — 610 41,700 23 melt CAB-O-SIL20 2870 174,100 extrusionThese results show that the adsorbate of Example 21 provided aC_(max,90) that was 5.8-fold that of the Control 4 and a AUC₉₀ that was3.9 fold that of Control 4.

Example 23

A 20% Drug 4/CAB-O-SIL M-5P adsorbate was produced using melt extrusiontechnology. A preblend of 80 wt % CAB-O-SIL M-5P and 20 wt % Drug 4 wasfed into a 19 mm co-rotating twin screw extruder (B&P Process EquipmentTC-19, 25 L/D) operating at 30 rpm. The feed rate was 10 g/min from anAccurate 304-12 volumetric feeder. The extruder was set up to act as acontinuous, mixed heat exchanger. The screw configuration consisted oftwin lead feed screw elements and mixing paddles set up as forwardmixing elements. This setup allowed for filled screw sections for heattransfer from the barrel and avoidance of excessive flow restriction.The die area of the extruder was left open, also to avoid flowrestriction. The barrel temperature was ramped from 25° C. at the feedarea to 170° C. in the last barrel zone (discharge end). The extrudatewas discharged into ambient air, resulting in rapid solidification ofthe drug on the substrate.

Example 24

The adsorbate of Example 23 was evaluated in the in vitro dissolutiontest described in Example 22. In this test, 45 mg of the adsorbate ofExample 23 was added to the microcentrifuge tubes used in the test.Samples for this test were collected at 4, 10, 20, 40, 90, and 1200minutes. The concentrations of drug obtained in these samples are shownin Table 24A. TABLE 24A Drug 4 Time Concentration AUC Example (min)(μgA/mL) (min * μg/mL) 23 0 0 0 4 2800 5,600 10 2870 22,600 20 198046,900 40 1830 84,900 90 1740 174,100 1200 1620 2,039,000The results of this test are summarized in Table 22B and show that theadsorbate of Example 23 provided a C_(max,90) that was 4.7-fold and anAUC₉₀ that was 4.2-fold that obtained for Control 4. Comparison of theresults for Example 21 and Example 23 indicates that adsorbates of Drug4 and CAB-O-SIL M-5P produced by spray drying and extrusion performssimilarly.

Example 25

The physical stability of the adsorbate of Example 23 was evaluated bystoring samples of the adsorbate at 40° C. and 75% relative humidity andperiodically withdrawing samples and analyzing them by PXRD. After 4days of storage, the drug in the adsorbate of Example 23 was about 5%crystalline, yielding a crystallization rate of 1.25%/day, whereas anamorphous control had a crystallinity of more than 80% under the sameconditions, yielding a crystallization rate of 20%/day. Thus, theadsorbate of Example 23 had improved physical stability compared to thecontrol, having a crystallization rate that was only about 6% of thecontrol.

Example 26

The adsorbates of Example 21 and Example 23 were analyzed by FTIR asdescribed in Example 16. The FTIR spectra showed that Drug 4 in theadsorbate is hydrogen bonded to the surface of the silicon dioxideparticles. This was indicated by a shift of the carbonyl bond(identified in amorphous Drug 4 at approximately 1740 cm-⁻¹) to a 20cm⁻¹ lower energy state.

Example 27

A drug/substrate adsorbate was produced using a rotovapping process thatslowly removed solvent from the suspension. In this technique, 450 mgCAB-O-SIL M-5P was sonicated for 15 min in 26.25 g of acetone using thesonication equipment described in Example 6. 150 mg of Drug 2 was thenadded and the suspension was allowed to equilibrate for 20 minutes,followed by an additional 5 minutes of sonication resulting indissolution of the drug in the suspension. The suspension was rotovappedin a waterbath that was thermally stabilized at 40° C. The sample wasdried under vacuum over night. The rotovapping process yielded about 88%adsorbate product. After drying, the Example 27 adsorbate contained 25wt % Drug 2 and 75 wt % CAB-O-SIL M-5P.

Example 28

The adsorbate of Example 27 was evaluated using an NMR test using theprocedures described in Example 11. The results of this test arepresented in Table 28, along with the results for the spray driedadsorbate of Example 9 and the crystalline Control 2A. These data showthat the rotovapped adsorbate of Example 27 provided an enhanced Drug 2concentration compared with the crystalline Control 2A. The data alsoshows that the spray dried adsorbate of Example 9 provided even greaterenhancement. TABLE 28 Drug 2 Conc. Dissolved Method of in the Drug 2Preparing Adsorbate Concentration Example Substrate Adsorbate (wt %)(μgA/mL) 27 CAB-O-SIL slow 25 13 M-5P evaporation (90 minutes)rotovapping)  9 CAB-O-SIL rapid 25 59 M-5P solvent (90 minutes) removal(spray- drying) Control 2A none — — 0 (crystalline (60 minutes control)and 240 minutes)

Example 29

This example illustrates that combining concentration-enhancing polymerwith an adsorbate results in improved concentration enhancement. Theadsorbate of Example 1 was evaluated in an in vitro dissolution testusing the procedure described in Example 2, except that 18 mg of theadsorbate was added to a microcentrifuge tube containing 1.8 mL PBS with5.4 mg hydroxypropyl methyl cellulose (HPMC) (theconcentration-enhancing polymer). The results are presented in Table29A. TABLE 29A Drug 1 Time Concentration AUC Example (min) (μg/mL)(min * μg/mL) 29 0 0 0 4 1157 2,300 10 1228 9,500 20 1348 22,300 40 135549,400 90 1404 118,400 1200 1164 1,543,600

The results of this test are summarized in Table 29B which also includesdata for dissolution tests with the adsorbate of Example 1 withoutconcentration-enhancing polymer. TABLE 29B Drug 1 Conc. in the AUC₉₀Adsorbate Receptor C_(max,90) (min * Example Substrate (wt %) Solution(μgA/mL) μg/mL) 29 zinc oxide 10 PBS/HPMC 1404 118,400 1 zinc oxide 10PBS 1098 69,900These results show that the adsorbate mixed with concentration-enhancingpolymer in Example 29, provided a C_(max,90) value that was 1.3-foldthat provided by the adsorbate alone. The adsorbate mixed withconcentration-enhancing polymer also provided an AUC₉₀ that was 1.7-foldthat provided by the adsorbate alone.

Example 30

The adsorbate of Example 17 was evaluated in an in vitro dissolutiontest using the procedure described in Example 18, except that 1.44 mg ofthe adsorbate was added to a microcentrifuge tube containing 1.8 mL 0.5wt % MDF solution with 1.08 mg of the concentration-enhancing polymerHPMCAS-HF. The results are presented in Table 30A. TABLE 30A Drug 3 TimeConcentration AUC Example (min) (μg/mL) (min * μg/mL) 30 0 0 0 4 44 8810 23 290 20 18 490 40 16 820 90 14 1,600 1200 10 14,600

The results of this test are summarized in Table 30B, along with resultsof dissolution tests with the adsorbate without concentration-enhancingpolymer (see Example 18). TABLE 30B Drug 3 Conc. in the AUC₉₀ Ex-Adsorbate Receptor C_(max,90) (min * ample Substrate (wt %) Solution(μgA/mL) μg/mL) 30 CAB-O-SIL 25 0.5% MFD/ 44 1600 M-5P HPMCAS-HF 17CAB-O-SIL 25 0.5% MFD 8 320 M-5PThese results show that the adsorbate mixed with aconcentration-enhancing polymer (Example 30) provided a C_(max,90) valuethat was 5.5-fold that of the adsorbate alone (Example 17). Theadsorbate mixed with a concentration-enhancing polymer also provided anAUC₉₀ value that was 5.0-fold that of the adsorbate alone.

Example 31

A drug/concentration-enhancing polymer/substrate adsorbate of Drug 2,HPMCAS-MF and CAB-O-SIL M-5P was prepared by first mixing a “mediumfine” (AQUOT-MF) grade of the ionizable cellulosic polymer HPMCAS(manufactured by Shin Etsu, Tokyo, Japan) in solvent and sonicatinguntil fully in solution. CAB-O-SIL M-5P was then added and the solutionwas sonicated for at least 10 minutes. Then Drug 2 was added and thesolution was sonicated a third time until the drug fully dissolved. Theresulting suspension consisted of 0.31 wt % Drug 2,1.84 wt % CAB-O-SILM-5P, 0.92 wt % HPMCAS, and 96.93 wt % acetone. The spray solution wasthen pumped into a “mini” spray-drying apparatus via a Cole Parmer 74900series rate-controlling syringe pump at a rate of 0.83 mL/min. Thespray-drying apparatus was a Spraying Systems Co. two-fluid nozzle,model number SULA, with nitrogen as the atomizing gas. The nitrogen waspressurized and heated to a temperature of 120° C. at a flow rate ofabout 1 scfm. The solution was sprayed from the top of an 11 centimeterdiameter stainless steel chamber. The resulting solid amorphousadsorbate was collected on Whatman® 1 filter paper, dried under vacuum,and stored in a dessicator. After drying, the Example 31 adsorbatecontained 10 wt % Drug 2, 60 wt % CAB-O-SIL M-5P, and 30 wt % HPMCAS-MFpolymer.

Example 32

The adsorbate of Example 31 was evaluated in an in vitro dissolutiontest using the procedure described in Example 7, except that 18 mg ofthe adsorbate was added to a microcentrifuge tube containing 1.8 mL 0.5wt % MFD solution at pH 6.5 The results are presented in Table 32A.TABLE 32A Drug 2 Time Concentration AUC Example (min) (μg/mL) (min *μg/mL) 31 0 0 0 4 70 140 10 100 650 20 190 2,100 40 230 6,290 90 28619,200 1200 92 228,800

The results of this test are summarized in Table 32B, along with theresults for the adsorbate of Example 6 tested without aconcentration-enhancing polymer (see Example 7). TABLE 32B Drug/Substrate/ Polymer in the Adsorbate C_(max,90) AUC₉₀ Example Substrate(wt %) (μg/mL) (min * μg/mL) 31 CAB-O-SIL 10/60/30 286 19,200 M-5P 6CAB-O-SIL 10/90/0 89 1,400 M-5P 33 CAB-O-SIL 33^(1/3)/ 78 4,600 M-5P33^(1/3)/ 33^(1/3)

Example 33

A drug/concentration-enhancing polymer/substrate adsorbate of Drug 2,HPMCAS-MG, and CAB-O-SIL M-5P was prepared by first mixing Drug 2 in asolvent together with a “medium granular” (AQUOT-MG) grade of theionizable cellulosic polymer HPMCAS (manufactured by Shin Etsu) to forma solution. CAB-O-SIL M5P was then suspended in the Drug 2/HPMCASmixture. The suspension consisted of 2.5 wt % Drug 2, 2.5 wt % CAB-O-SILM-5P, 2.5 wt % HPMCAS, and 92.5 wt % acetone. The solution was sprayedas described in Example 31. After drying, the Example 33 adsorbatecontained 33 wt % Drug 2, 33 wt % CAB-O-SIL M-5P, and 33 wt % HPMCAS-MGpolymer.

Example 34

Example 33 was evaluated in an in vitro dissolution test using theprocedure describe in Example 7, except that 5.4 mg of the adsorbate wasadded to a microcentrifuge tube containing 1.8 mL 0.5 wt % MFD solutionat pH 6.5. The results are presented in Table 34A and summarized inTable 32B. TABLE 34A Drug 2 Time Concentration AUC Example (min) (μg/mL)(min * μg/mL) 33 0 0 0 4 47 94 10 39 352 20 43 760 40 43 1,600 90 784,600 1200 37 68,600

Example 35

A drug/substrate adsorbate of Drug 3 and CAB-O-SIL EH-5 was prepared byusing the procedure outlined in Example 17 with the followingexceptions. The suspension consisted of 0.67 wt % CAB-O-SIL, 0.22 wt %Drug 3, and 99.11 wt % tetradrofuran. The CAB-O-SIL was added to thesolvent and then sonicated for 45 minutes to ensure full suspension andhomogeneity. After drying, the Example 35 adsorbate contained 25 wt %Drug 3 and 75 wt % CAB-O-SIL.

Control 3B: Control 3B consisted of the amorphous form of Drug 3 withouta substrate.

Example 36

The drug/substrate adsorbate of Example 35 was evaluated in an in vitrodissolution test using the procedure described in Example 18, exceptthat 1.44 mg of the adsorbate, or 0.36 mg of Control 3B, was added to amicrocentrifuge tube containing 1.8 mL 0.5 wt % MFD solution at pH 6.5.The results are presented in table 36A and summarized in Table 36B.TABLE 36A Drug 3 Time Concentration AUC Example (min) (μgA/mL) (min *μg/mL) 35 0 0 0 4 22 0 10 16 200 20 15 300 40 14 600 90 13 1,300 1200 1516,800 Control 3B 0 0 0 4 2 0 10 2 0 20 2 0 40 2 100 90 2 200 1200 22,400

The results show that the C_(max,90) provided by the adsorbate ofExample 35 was 11-fold that of Control 3B while the AUC₉₀ was 6.5-foldthat of Control 3B. TABLE 36B Drug/ Substrate in the AUC₉₀ AdsorbateC_(max,90) (min * C₁₂₀₀ Example Substrate (wt %) (μgA/mL) μg/mL)(μgA/mL) 35 CAB-O-SIL 25/75 22 1300 15 EH-5 Control 3B none — 2 200 2

Example 37

A drug/concentration-enhancing polymer/substrate adsorbate of Drug 3,cellulose acetate phthalate (CAP)(NF grade, Eastman Chemical Co.,Kingsport, Tenn.), and CAB-O-SIL M-5P was prepared by using theprocedure outlined in Example 31 with the following exceptions. Thesuspension consisted of 0.11 wt % Drug 3, 0.20 wt % CAB-O-SIL M-5P, 0.20wt % CAP, and 99.49 wt % methanol/acetone (2/1). The spray solution waspumped at a rate of 1.0 mL/min, and the nitrogen gas was heated to 100°C. After drying, the Example 37 adsorbate contained 20 wt % Drug 3, 40wt % CAB-O-SIL M-5P, and 40 wt % CAP polymer.

Example 38

The drug/concentration-enhancing polymer/substrate adsorbate of Example37 was evaluated in an in vitro dissolution test using the proceduredescribed in Example 18, except that 1.96 mg of the adsorbate, or 0.39mg of Control 3A, was added to a microcentrifuge tube containing 1.8 mL0.5 wt % MFD solution at pH 6.5. The results are presented in Table 38Aand summarized in Table 38B. TABLE 38A Drug 3 Time Concentration AUCExample (min) (μgA/mL) (min * μg/mL) 37 0 0 0 4 74 100 10 70 600 20 51,000 40 4 1,000 90 3 1,200 1200 3 4,600 Control 3A 0 0 0 4 13 0 10 22100 20 26 400 40 13 800 90 8 1,300 1200 9 10,700

The results show that the C_(max,90) provided by the adsorbate ofExample 37 was 2.8-fold that of Control 3A. TABLE 38B Drug/ Substrate/Polymer in the AUC₉₀ Adsorbate C_(max,90) (min * C₁₂₀₀ Example Substrate(wt %) (μgA/mL) μg/mL) (μgA/mL) 37 CAB-O-SIL 20/40/40 74 1200 3 M-5PControl 3A none — 26 1300 9

Example 39

This example illustrates that combining concentration-enhancing polymerwith a drug/substrate adsorbate results in improved concentrationenhancement. The adsorbate of Example 9, consisting of 25 wt % Drug 2and 75 wt % CAB-O-SIL M-5P, was evaluated in an in vitro dissolutiontest using the procedure describe in Example 2, except that 7.2 mg ofthe adsorbate, or 1.8 mg of Control 2B, was added to a microcentrifugetube containing 1.8 mL PBS alone, or 1.8 mL PBS with 3.6 mg of theconcentration-enhancing polymer polyoxyethylene-polyoxypropylene blockcopolymer (Pluronic® F-127, available from BASF Corp.) HPLC analysis ofDrug 2 was performed as described in Example 7. The results presented inTable 39A. TABLE 39A Drug 2 Time Concentration AUC Example (min)(μgA/mL) (min * μg/mL) Example 9 0 0 0 4 23 0 10 5 100 20 3 200 40 2 20090 1 300 1200 2 2,200 Example 9 + Pluronic 0 0 0 F127 4 33 100 10 30 30020 39 600 40 47 1,500 90 72 4,400 1200 71 83,800 Control 2B 0 <1 0 4 <1<2 10 <1 <8 20 <1 <18 40 <1 <38 90 <1 <88 1200 <1 <1,200

The results of this test are summarized in table 39B. TABLE 39B Drug 2Conc. in the AUC₉₀ Adsorbate Receptor C_(max,90) (min * ExampleSubstrate (wt %) Solution (μgA/mL) μg/mL) 9 CAB-O-SIL 25 PBS 23 300 M-5P9 + Pluronic CAB-O-SIL 25 PBS 72 4400 F127 M-5P Control 2B none 100 PBS<1 <88

These results show that the adsorbate of Example 9 mixed with theconcentration-enhancing polymer Pluronic F127, provided a C_(max,90)value that was 3.1-fold that provided by the adsorbate alone, and aC_(max,90) value that was greater than 72-fold that provided by Control2B. The adsorbate mixed with concentration-enhancing polymer alsoprovided an AUC₉₀ that was 11-fold that provided by the adsorbate alone,and an AUC₉₀ that was greater than 50-fold that provided by Control 2B.

Example 40

A drug/substrate adsorbate of sildenafil citrate (Drug 5) was producedusing the procedure outlined in Example 6 with the following exceptions.The suspension consisted of 0.58 wt % CAB-O-SIL M-5P, 0.09 wt % Drug 5,and 99.33 wt % methanol. The nitrogen gas was heated to 100° C. Afterdrying, the Example 40 adsorbate contained 10 wt % active Drug 5.

Control 5: Control 5 was crystalline Drug 5 alone.

Example 41

The drug/substrate adsorbate of Example 40 was evaluated in an in vitrodissolution test using the procedure described in Example 2, except that12.91 mg of the adsorbate, or 1.29 mg of Control 5, was added to amicrocentrifuge tube containing 1.8 mL PBS alone, or 1.8 mL PBS with 2.7mg of the concentration-enhancing polymer CAP. HPLC analysis wasperformed using a Waters Symmetry C₈ column, with a mobile phase of0.05M TEA, pH 3.0/methanol/acetonitrile (58/25/17). UV absorbance ofDrug 5 was measured at 290 nm. The results presented in Table 41A. TABLE41A Drug 5 Time Concentration AUC Example (min) (μgA/mL) (min * μg/mL)Example 40 0 0 0 4 40 100 10 36 300 20 38 700 40 44 1,500 90 37 3,5001200 37 44,600 Example 40 + 0 0 0 CAP 4 146 300 10 151 1,200 20 1622,700 40 162 6,000 90 172 14,300 1200 145 190,300 Control 5 0 0 0 4 42100 10 40 300 20 47 800 40 47 1,700 90 42 3,900 1200 31 44,400

The results of this test are summarized in table 41B. TABLE 41B Drug 5Conc. in the Re- C_(max,90) AUC₉₀ C₁₂₀₀ Adsorbate ceptor (μgA/ (min *(μgA/ Example Substrate (wt %) Solution mL) μg/mL) mL) 40 CAB-O-SIL 10PBS 44 3500 37 M-5P 40 + CAP CAB-O-SIL 10 PBS 172 14,300 145 M-5PControl 5 none 100 PBS 47 3900 31These results show that the adsorbate of Example 40 mixed with theconcentration-enhancing polymer CAP provided a C_(max,90) value that was3.7-fold that provided by Control 5. The adsorbate mixed withconcentration-enhancing polymer also provided an AUCgo that was 3.7-foldthat provided by Control 5.

Example 42

A drug/concentration-enhancing polymer/substrate adsorbate consisting ofDrug 2, polyoxyethylene-polyoxypropylene block copolymer (Pluronic Fl27), and CAB-O-SIL M-5P was prepared using the procedure outlined inExample 31 with the following exceptions. The suspension consisted of0.39 wt % Drug 2, 0.78 wt % CAB-O-SIL M-5P, 0.78 wt % Pluronic Fl 27,and 98.05 wt % acetone. The spray solution was pumped at a rate of 1.2mL/min, and the nitrogen gas was heated to 100° C. After drying, theadsorbate of Example 42 contained 20 wt % Drug 2, 40 wt % CAB-O-SILM-5P, and 40 wt % Pluronic F127 polymer.

Example 43

The drug/concentration-enhancing polymer/substrate adsorbate of Example42 was evaluated in an in vitro dissolution test using the proceduredescribed in Example 2, except that 9.0 mg of the adsorbate, or 1.8 mgof Control 2B, was added to a microcentrifuge tube containing 1.8 mL PBSsolution at pH 6.5. HPLC analysis of Drug 2 was performed as describedin

Example 7. The results presented in Table 43A and summarized in Table43B. TABLE 43A Drug 2 Time Concentration AUC Example (min) (μgA/mL)(min * μg/mL) 42 0 0 0 4 173 300 10 168 1,400 20 163 3,000 40 158 6,20090 145 13,800 1200 64 129,800 Control 2B 0 <1 0 4 <1 <2 10 <1 <8 20 <1<18 40 <1 <38 90 <1 <88 1200 <1 <1,200

The results of this test are summarized in Table 43B. These results showthat the C_(max,90) providede by the adsorbate of Example 42 was greaterthan 173-fold that of Control 2, and the AUC₉₀ was greater than 157-foldthat of Control 2. TABLE 43B Drug/ Substrate/ Polymer in AUC₉₀ C₁₂₀₀ theAdsorbate C_(max,90) (min * (μgA/ Example Substrate (wt %) (μgA/mL)μg/mL) mL) 42 CAB-O-SIL 20/40/40 173 13,800 64 M-5P Control 2B none — <1<88 <1

Example 44

A drug/substrate adsorbate of Drug 2 and CAB-O-SIL M-5P was preparedusing the procedure outlined in Example 6 with the following exceptions.The suspension consisted of 0.86 wt % CAB-O-SIL M-5P, 0.29 wt % Drug 2,and 98.85 wt % acetone. The spray solution was pumped at a rate of 1.2mL/min, and the nitrogen gas was heated to 100° C. After drying, theExample 44 adsorbate contained 25 wt % Drug 2 and 75 wt % CAB-O-SILM-5P.

Example 45

The drug/substrate adsorbate of Example 44 was dosed in the form of anoral powder for constitution (OPC) to evaluate the composition in invivo tests using male beagle dogs. The OPC was dosed as a suspension ina solution containing 0.5 wt % Methocel® (Dow Chemical Co.), and wasprepared as follows. First, 7.5 g of Methocel® was weighed out and addedslowly to approximately 490 ml of water at 90°-100° C. to form aMethocel® suspension. After all the Methocel® was added, 1000 mL ofcool/room temperature water was added to the suspension, which was thenplaced in an ice-water bath.

When all of the Methocel®D had dissolved, 2.55 g of Tween 80 were addedand the mixture stirred until the Tween 80 had dissolved, thus forming astock suspension solution.

To form the OPC, sufficient quantity of the test composition to resultin a 90 mgA amount of Drug 2 was accurately weighed and placed into amortar. A 20-mL quantity of the stock suspension solution was added tothe mortar and the test composition was mixed with a pestle. AdditionalMethocel® suspension was added gradually with mixing until a total of400 mL of the stock suspension solution had been added to the mortar.The suspension was then transferred to a flask, thus forming the OPC. Inaddition, an OPC containing 90 mgA of amorphous Drug 2 (Control 2B) wasprepared using the same procedure.

Six male beagle dogs were each dosed with the OPC using a gavage tubeand a syringe. Whole blood samples were taken from the jugular vein and30 analyzed for the concentration of Drug 2. To 25 μL of each plasmasample, 30 μL of Drug 2 internal standard solution was added and sampleswere vortexed.

Next, 1.0 mL acetonitrile was added, and samples were vortexed,centrifuged, and added to glass culture tubes. To each tube, 100 μL 1.0M KH₂PO₄ buffer, pH 11, and 20 μL PFBBr was added. Samples were vortexedand incubated for 30 minutes at 85° C. To each tube, 2.0 mL water and0.5 mL methyl tert-butyl ether was added, and samples were vortexed,centrifuged, and 100 μL removed and added to GC vials. Analysis wascarried out by GC The results of these tests are presented in Table 45and show that the compositions of the present invention providedenhanced drug concentration and relative bioavailability relative to theamorphous Drug 2 control (Control 2B). The composition of Example 44dosed to fasted beagle dogs provided a C_(max) that was more than423-fold that of the amorphous control, and a relative bioavailabilitythat was greater than 8400 relative to the amorphous control. Thecomposition of Example 44 dosed to fed beagle dogs provided a C_(max)that was 6.8-fold that of the amorphous control, and a relativebioavailability that was 7.3 relative to the amorphous control. TABLE 45Composition C_(max) (ng/ml) AUC₍₀₋₂₄₎ (ng/ml * hr) Example 44 (25 wt %Drug 2/ 427.8 1687.4 CAB-O-SIL M-5P)- fasted Control 2B (amorphous Drug<0.1 <0.2 2) - fasted Example 44 (25 wt % Drug 2/ 1254.9 4365.0CAB-O-SIL M-5P)- fed Control 2B (amorphous Drug 184.8 598.5 2) - fed

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

1-22. (canceled)
 23. A pharmaceutical composition comprising: (a) asolid adsorbate comprising a low-solubility drug adsorbed onto asubstrate, said substrate having a surface area of at least 20 m²/g,wherein at least 60 wt % of said drug in said adsorbate is amorphous;(b) a concentration-enhancing polymer; and (c) wherein said drug is acholesteryl ester transfer protein inhibitor.
 24. The composition ofclaim 23 wherein said polymer and said drug are co-adsorbed to saidsubstrate.
 25. The composition of claim 23 wherein said polymer and saidsolid adsorbate are physically mixed.
 26. The composition of claim 23wherein said drug in said adsorbate has a glass transition temperaturesubstantially different from that of said drug in amorphous form alonethat is not adsorbed to said substrate.
 27. The composition of claim 23wherein said drug has improved physical stability in said adsorbaterelative to a control composition consisting of an equivalent amount ofsaid drug in amorphous form alone that is not adsorbed to saidsubstrate.
 28. The composition of claim 23 wherein said drug and saidpolymer comprise an amorphous dispersion, and said dispersion issubstantially homogeneous.
 29. The composition of claim 23 wherein saidpolymer is selected from the group consisting of hydroxypropyl methylcellulose succinate, cellulose acetate succinate, methyl celluloseacetate succinate, ethyl cellulose acetate succinate, hydroxypropylcellulose acetate succinate, hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropyl cellulose acetate phthalate succinate,cellulose propionate succinate, hydroxypropyl cellulose butyratesuccinate, hydroxypropyl methyl cellulose phthalate, carboxymethylcellulose, carboxyethyl cellulose, ethylcarboxymethyl cellulose,cellulose acetate phthalate, methyl cellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate, carboxylic acid functionalizedpolymethacrylates, carboxylic acid functionalized polyacrylates,amine-functionalized polyacrylates, amine-fuctionalizedpolymethacrylates, proteins, and carboxylic acid functionalizedstarches, hydroxypropyl methyl cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose, vinyl polymers and copolymers having at least one substituentselected from the group consisting of hydroxyl, alkylacyloxy, andcyclicamido, vinyl copolymers of at least one hydrophilic,hydroxyl-containing repeat unit and at least one hydrophobic, alkyl- oraryl- containing repeat unit, polyvinyl alcohols that have at least aportion of their repeat units in the unhydrolyzed form, polyvinylalcohol polyvinyl acetate copolymers, polyethylene glycol polypropyleneglycol copolymers, polyvinyl pyrrolidone, polyethylene polyvinyl alcoholcopolymers, polyoxyethylene-polyoxypropylene block copolymers,neutralized forms thereof, and blends thereof.
 30. The composition ofclaim 23 wherein said concentration-enhancing polymer is selected fromthe group consisting of hydroxy propyl methyl cellulose acetatesuccinate, hydroxy propyl methyl cellulose phthalate, cellulose acetatephthalate, cellulose acetate trimellitate, carboxyethyl cellulose,carboxymethyl cellulose, and ethyl carboxymethyl cellulose.
 31. Thecomposition of claim 23 wherein said concentration-enhancing polymer isa non-ionizable, non-cellulosic polymer selected from the groupconsisting of vinyl polymers or copolymers having at least onesubstituent selected from the group consisting of hydroxyl,alkylacyloxy, and cyclicamido, vinyl copolymers of at least onehydrophilic, hydroxyl-containing repeat unit and at least onehydrophobic, alkyl- or aryl- containing repeat unit, polyvinyl alcoholsthat have at least a portion of their repeat units in the unhydrolyzedform, polyvinyl alcohol polyvinyl acetate copolymers, polyethyleneglycol polypropylene glycol copolymers, polyvinyl pyrrolidone,polyethylene polyvinyl alcohol copolymers,polyoxyethylene-polyoxypropylene block copolymers and blends thereof.32. The composition of claim 23 wherein said polymer is polyvinylpyrrolidone.
 33. The composition of claim 23 wherein said compositionwhen administered to a use environment provides at least one of: (a) adissolution area under the concentration versus time curve for a timeperiod of at least 90 minutes between the time of introduction to saiduse environment and about 270 minutes following introduction to the useenvironment that is at least 1.25-fold the corresponding area under thecurve provided by a control composition comprising an equivalent amountof crystalline drug alone; (b) a maximum concentration of said drug insaid use environment that is at least 1.25-fold a maximum concentrationof said drug provided by said control composition comprising anequivalent amount of crystalline drug alone; and (c) a relativebioavailability of at least 1.25 relative to said control compositionconsisting of an equivalent amount of said drug in crystalline formalone.
 34. The composition of claim 23 wherein said substrate isselected from the group consisting of inorganic oxides, zeolites,molecular sieves, and mixtures thereof;
 35. The composition of claim 23wherein said substrate is selected from the group consisting of SiO₂,TiO₂, ZnO₂, ZnO, Al₂O₃, and zeolite.
 36. The composition of claim 35wherein said concentration-enhancing polymer is selected from the groupconsisting of hydroxy propyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate,cellulose acetate trimellitate, carboxyethyl cellulose, carboxymethylcellulose, and ethyl carboxymethyl cellulose.
 37. The composition ofclaim 35 wherein said concentration-enhancing polymer is selected fromthe group consisting of vinyl polymers or copolymers having at least onesubstituent selected from the group consisting of hydroxyl,alkylacyloxy, and cyclicamido, vinyl copolymers of at least onehydrophilic, hydroxyl-containing repeat unit and at least onehydrophobic, alkyl- or aryl- containing repeat unit, polyvinyl alcoholsthat have at least a portion of their repeat units in the unhydrolyzedform, polyvinyl alcohol polyvinyl acetate copolymers, polyethyleneglycol polypropylene glycol copolymers, polyvinyl pyrrolidone,polyethylene polyvinyl alcohol copolymers,polyoxyethylene-polyoxypropylene block copolymers and blends thereof.38. The composition of claim 23 wherein said substrate is SiO₂.
 39. Thecomposition of claim 23 wherein said cholesteryl ester transfer proteininhibitor has a minimum aqueous solubility of less than 0.1 mg/mL at apH of 1 to
 8. 40. The composition of claim 23 wherein said cholesterylester transfer protein inhibitor is selected from the group consistingof [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2R, 4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and propanethioic acid, 2-methyl-S-[2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl] ester.
 41. The composition of claim 23 whereinsaid drug is(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.42. The composition of claim 23 wherein said drug is(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol,said substrate is SiO2, and said polymer is polyvinyl pyrrolidone. 43.The composition of claim 23 wherein said drug is(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol,said substrate is SiO₂, and said polymer is hydroxypropyl methylcellulose acetate succinate.
 44. A method for forming a pharmaceuticalcomposition, comprising: (a) providing a substrate having a surface areaof at least 20 m²/g; (b) adding said substrate to a solvent to form asuspension and agitating said suspension; (c) dissolving alow-solubility drug in said solvent; (d) rapidly removing said solventfrom said suspension to form a rapidly quenched adsorbate comprisingsaid low-solubility drug adsorbed onto said substrate, wherein at leasta major portion of said drug in said adsorbate is in amorphous form; and(e) wherein said drug is a cholesteryl ester transfer protein inhibitor.45. A method for forming a pharmaceutical composition, comprising: (a)providing a substrate having a surface area of at least 20 m²/g; (b)melting a low-solubility drug; (c) combining said low-solubility drugwith said substrate to form a mixture; (d) cooling said mixture so thatsaid low-solubility drug is adsorbed onto said substrate to form anadsorbate, at least a major portion of said drug in said adsorbate beingin amorphous form; and (e) wherein said drug is a cholesteryl estertransfer protein inhibitor.
 46. The method of any one of claims 44 and45 further comprising the step of combining a concentration-enhancingpolymer with said low-solubility drug and said substrate.